Development 99, 449-471 (1987)
Printed in Great Britain © The Company of Biologists Limited 1987
Review Article
449
Oncogenes in development
EILEEN D. ADAMSON
La Jolla Cancer Research Foundation, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Synopsis
Section no.
(1) Introduction
(2) EGF receptor/c-erb-B
(3) CSF-1 receptor/c-/nw
(4) c-src
(5) c-abl
(6) Other oncogene kinases
(7) The ras family of genes
(8) c-fos
(9) c-myb
page
449
449
452
452
453
454
454
455
457
(1) Introduction
Realization that the transforming oncogenes (v-onc)
of the acutely oncogenic retroviruses are homologous
to cellular genes (and were probably derived from
them) brought several areas of research together with
exciting prospects for advances in virology, carcinogenesis, evolution and development. The proto-oncogenes (c-onc) are likely to be crucially involved in
growth regulation and/or differentiation because of
their conservation throughout evolution and because
of the well-known growth deregulation effects produced by the \-oncs. It was therefore reasoned that
the normal counterpart of these genes should be
active during embryonic development and that identification of a specific tissue or stage where c-oncs are
expressed should help to identify their roles in all cells
and provide a source of material to study the mechanisms of action. The preliminary results suggest growth
modulatory roles for most oncogenes, and developmental studies have provided clues to c-onc roles that
would not have been forthcoming from studies on cell
lines.
Several c-onc products have now been identified
with specific cellular proteins, and these have confirmed their importance to growth regulation. They
are growth factor or hormone receptors (such as
c-erb-B, or epidermal growth factor [EGF] receptor;
c-fms, or colony stimulating factor-1 [CSF-1] receptor
(10)
(11)
(12)
(13)
The myc gene family
c-sis
Other proto-oncogenes
Proto-oncogene expression in teratocarcinoma cells
(14) Conclusions and summary
(15) References
457
459
460
460
461
462
Kev words: oncoeene.
and c-erb-A, or thyroid hormone receptor) or growth
factors (such as c-sis, or B chain of the plateletderived growth factor [PDGF]). Table 1 lists the
proto-oncogenes that have been studied in developing or differentiating systems. For general reviews,
see Miiller, 1983; Hunter, 1984; Weinberg, 1984;
Varmus, 1984; Heldin & Westermark, 1984; Sinkovics, 1984; Klein & Klein, 1985; Bishop, 1985; and
Muller, 1986.
(2) EGF receptor/c-erf>-B
The best known of the tyrosine kinase family
of c-oncs is the EGF receptor, which is a larger
homologue of the v-erb-B protein that causes avian
erythroblastosis in chickens infected with avian erythroblastosis virus (AEV) (Downward etal. 1984). The
EGF receptor has been recognized as a cell-surface
glycoprotein whose activity is triggered after binding
EGF in the cellular environment. After receptor
clustering and endocytosis, lysosomal compartments
degrade both receptor and ligand. After this event
there is very little known about how the cell receives
the signal to commence DNA synthesis and to enter
mitosis. Many steps of the process may be necessary,
but after the discovery that the receptor also has a
tyrosine phosphokinase enzyme activity (Ushiro &
Cohen, 1985) that leads to the phosphorylation of
itself and of other cellular substrates, the clearest clue
450
E. D. Adamson
Table 1. Some proto-oncogenes and their protein products
Chromosomal
location
human/
mouse
References
Protein identity,
c-onc
homology or size
I. Tyrosine kinase and related c-onc
c-erb-B
EGF receptor
170 K
Cell location and
distribution
Activities
Possible roles
Plasma membrane of
mesodermal, ectodermal
& endodermal cells
EGF binding
TGFa binding
Tyr. kinase
Signal transductionfor
mitogenesis and differ".
Stim° of tooth eruption,
eye-opening, lung devel.
7/7
1
c-neu
185 K
Homology to EGF-R
Plasma membrane
Tyr. kinase
Receptor for an
unknown ligand?
17/?
2.
c-fms
CSF-1 receptor
140 K
Plasma membrane of
macrophages & extraembryonic cells
CSF-1 binding
Try. kinase
Signal transduction for
mitogenesis and differ"
5/?
3.
c-src
60K
Cytoplasmic face of
membranes.
Adhesion plaques
Tyr. kinase
phosphorylates
many cellular
proteins, e.g.,
vinculin, vimentin,
filamin, p36.
Neurone &
muscle development9
20/9
4
c-mos
37K
Cytoplasmic.
Embryo
testis & ovary
Ser/thr kinase
8/?
5.
c-abl
150K
Plasma membrane
Tyr. kinase
phosphorylates
vincuhn
B-cell differ1?
9/7
6.
c-fes
c-fps
92 KJ
98 KJ
Cytoplasm, plasma
membrane
Tyr. kinase
Macrophage devel.9
15/ 9
7
II. GTPases
c-Ki-raj-2]
c-H-nu-1 \
21K
Membrane cytoplasmic
face in a wide
variety of cells
GTP + GDP
binding.
GTPase.
Adenylate cyclase
regulation?
10/7
11/7
1/7
8.
Nucleus of extraembryonic tissues,
haematopoietic cells
& macrophages All
other cells at lower
level.
DNA binding
with an accessory
protein
GO to Gl transition.
Differentiation
14/?
9.
62K
66K
Nuclear matrix of
most cells In some
tumours & embryonic
tissues.
DNA binding
Proliferation.
Regulates DNA
synthesis.
8/15
10.
75 K
Nucleus of haematopoietic cells
DNA binding
Differentiation of
haematopoietic cells9
6/?
11.
T3 receptor,
homology to
glucocorticoid
receptor
Cytoplasmic &
nuclear
Binds
thyroxine
Metabolic regulator?
17/7
12.
PDGF B chain
14 K
Secreted protein
Homo- or
heterodimer
binds to
PDGF-R
Mitogenesis
Wound healing
Early embryonic
growth factor?
22/7
13
III Nuclear products
c-fos
55 K
c-myc ^
N-myc 1
L-mycJ
c-myb
IV. O^ers
c-erfovl
c-iis
K, 10"3iMr
References
1. Hayman et al. 1983; Downward el al. 1984; Carpenter 1984. 2. Schechter a al. 1984, 1985; Hung el al. 1986. 3. Rettenmier et al. 1985; Coussens et al.
1986. 4. Purchio et al. 1978; Takeya & Hanafusa, 1983; Sejersenflo/. 1986. 5. Van Beveren et al. 1981; Papkoff«oA 1982, 1983; Baldwin, 1985. 6. Witte «
al 1978, 1979, 1980; Reddy a al. 1983. 7. Baibacid et at. 1980; Hampe et al. 1982; Caimier & Samarut, 1986; Ferrari et al. 1985. 8. Tsuchida a al. 1982;
Dhar et al. 1982; Hall et al. 1983; MOUer et al. 1982; Cooper a al. 1984. 9. Van Beveren et at. 1983; Deschamps et al. 1985. 10 Mellon et al. 1978; Alitalo et
al 1983; Kaczmarek et al. 1985: Eisenman a al. 1985; Wan et al. 1985; Jakobovitz et al. 1985; Zimmerman et al. 1986; Nau et al. 1985. U . G o n d a n a / .
1985; Sheiness & Gardinier, 1984; Janssen a al. 1986. 12 HoUenberg et al. 1983; Weinberger a al. 1985, 1986. 13. Devare et al. 1983; Doolittle et al. 1983.
appeared to have been identified. This is because the
proportion of phosphotyrosine, compared with phosphoserine and phosphothreonine in a normal cell, is
very small, about 0-03 % of the total. The mechanism
of oncogenesis via tyrosine phosphorylation has been
pursued vigorously, but the outcome so far has not
given a clear picture of the roles of tyrosine phosphokinases in growth regulation. For reviews that
Oncogenes in development
cover the enzymic and metabolic aspects of the EGF
receptor, see Thompson & Gill, 1985; Herschman,
1985; Kris, Libermann, Avivi & Schlessinger,
1985; Carpenter & Zendoqui, 1986; Soderquist &
Carpenter, 1986.
(2.1) The EGF-receptor gene
Normal tissues and cells appear to have a single gene
for EGF receptor but differential splicing leads to the
production of at least two mRNAs of about 6 and
10 kb (Ullrich et al. 1984; Lin et al. 1984; Xu et al.
1984). Both of these appear to code for full-length
protein of 170 x 103 Afr (170 K) (Simmen et al. 1984).
The gene is amplified in human A431 cells and in
several types of tumours such as gliomas (Libermann
et al. 1984), squamous cell carcinoma (Cowley et al.
1984) and retinoblastomas where the protein is also
overexpressed. Presumably the expression of high
levels of receptor provided a growth advantage to the
tumour cells but it is not known if this was the original
lesion.
(2.2) Distribution of EGF-binding activity in
developing tissues
EGF receptors are present on a wide range of cell
types including cells of ectodermal, mesodermal and
endodermal origin (reviewed by Adamson & Rees,
1981). They are also present on embryonic/fetal
tissues and extraembryonic tissues during murine
development (reviewed by Adamson, 1983). But in
spite of this, their role in development is not yet clear.
EGF receptors increase in number during the gestation period so that the new-born's liver expresses
more than any other tissue at any stage (Adamson &
Meek, 1984). Crude membrane preparations from all
fetal tissues (with the exception of the parietal yolk
sac) contain EGF-binding activity, and the affinity of
these receptors for 125I-EGF decreases somewhat
during development. The earliest time of detection is
on giant trophoblast cells of a 5-day blastocyst grown
for 2-3 days in culture (Adamson & Meek, 1984).
Fetal receptors are functional in that they bind EGF
and they can be down-regulated by excess EGF
injected into the placenta or amniotic cavity (Adamson & Warshaw, 1981). When fetal organs are
explanted and cultured with EGF, incorporation of
[3H]thymidine into DNA is stimulated (Adamson,
Deller & Warshaw, 1981). Autophosphorylating activity of EGF receptors is first detected in 10-day
mouse embryos at the time of onset of organogenesis
(Hortsch, Schlessinger, Gootwine & Webb, 1983).
The changing characteristics of EGF receptors
suggests that roles may be different at different stages
of development, although changing cell populations
could also explain changing receptor characteristics in
451
a tissue such as fetal liver which has high levels of
haemopoietic cells in the early stages.
Specific tissues have been targets of research aimed
to find a role for EGF in their development. EGF
stimulates skin differentiation in the neonatal mouse
and accelerates eye opening and tooth eruption
(Cohen, 1962). Palatal epithelium expresses EGF
receptors that may play a role in palate closure (Tyler
& Pratt, 1980; Turley, Hollenberg & Pratt, 1985).
Lung development and maturation are affected by
EGF (Catterton, Escobedo & Sexson, 1979; Gross et
al. 1986; Goldin & Opperman, 1980). Growth of
newborn rat liver, kidney and craniofacial structures
is retarded by EGF (Hoath, 1986). Chick neural crest
cells (Erickson & Turley, 1987), rat oocyte during
maturation (Dekel & Sherizly, 1985), and postnatal
and fetal development of rat gastric mucosa (Dembinski & Johnson, 1985; O'Loughlin et al. 1985;
Conteas, DeMorrow & Majumdar, 1986) are
influenced by EGF.
(2.3) Occurrence of EGF receptors in teratocarcinoma
cells
The stem cell lines (embryonal carcinoma, EC) of
murine teratocarcinomas appear to have very few
(F9) or no EGF-binding sites (OC15, PC13, P19).
When differentiation occurs, either in aggregate cultures (Adamson & Hogan, 1984) or in monolayers
(Rees, Adamson & Graham, 1979; Mummery et al.
1985), receptors appear which respond to EGF by
promoting cellular proliferation. Teratocarcinomaderived differentiated cell line PSA5E (visceral endoderm-like) also has EGF receptors, while PYS and
F9AC cells (parietal endoderm-like) do not. This
distribution is in agreement with the tissue distribution determined from embryo studies. Surprisingly, OC15 EC cells have considerable EGF-receptor-kinase activity (equivalent to about 3-day
differentiated cells), but it appears to be largely
intracellular or possibly masked (Weller, Meek &
Adamson, 1987). Therefore, we have to modify our
original hypothesis that early embryonic ectoderm
cells would be negative for this protein based on
findings in EC cells. Indeed, a human EC cell-line
(PA1) has been shown to express a low level of EGF
receptors on the cell surface (Carlin & Andrews,
1985).
(2.4) Activation of the EGF-receptor oncogene
protein during development
If the EGF receptor is to function it must receive
signals by ligand binding to the extracellular binding
domain. Two known growth factors bind to the EGF
receptor, EGF/urogastrone and transforming growth
factor a (TGFa). See reviews^ by Adamson (1983,
1986) and Roberts & Sporn (1985).
452
E. D. Adamson
(2.4.1) EGF
This 53 amino-acid polypeptide (6K) is synthesized
and stored in very large amounts in male adult mouse
(but not rat or human) submandibular salivary gland.
It is detected in saliva, amniotic fluid, milk, urine and
most tissues of several species. Although EGF has
been detected in fetal mice (Nex0, Hollenberg,
Figueroa & Pratt, 1980) and fetal rats (Matrisian,
Pathak & Magun, 1982), it seems unlikely to be
derived from the fetus itself, and Popliker et al. (1986)
have presented evidence that the EGF found in fetal
mice is derived from the mother. The EGF gene
occurs as a large gene encoding a precursor that
contains several EGF-like peptides as well as EGF,
together with a membrane-spanning domain (Scott et
al. 1983). Using a cloned probe for prepro EGF
mRNA, Rail et al. (1983) have shown high-level gene
transcription in the mouse salivary gland and in
kidney. Female kidney expresses about 2- to 4-fold
higher levels than male, and this is a reversal of the
salivary gland levels (Popliker et al. 1986; Gubits etal.
1986; Salido et al. 1986). However, only the salivary
gland precursor appears to be processed to the active
6K form. The kidney 130 K precursor form is not
known to be an active mitogen. The importance of
these reports is the realization that EGF is not
synthesized until at least 2 weeks postpartum in the
kidneys and even later (after weaning) in the male
salivary gland. Then why does the fetus express EGF
receptors?
(2.4.2) TGFa
Rat TGFar (5K) has been purified, sequenced, synthesized, molecularly cloned and shown to have
35-40 % homology with EGF (Marquardt, Hunkapillar, Hood & Todaro, 1983; Tarn et al. 1984; Lee,
Rose, Webb & Todaro, 19856). TGFa binds to EGF
receptors and produces exactly the same effects,
including mitogenesis and skin maturation. It can also
synergize with TGF/3 to stimulate anchorage-independent growth of normal fibroblasts. TGFa also
occurs as a larger precursor form (Derynck et al. 1984)
as a transmembrane protein. TGFa is found in
normal rat tissues (Lee et al. 19856; Stromberg,
Pigott, Ranchalis & Twardzik, 1982; Proper, Bjornson & Moses, 1982; Twardzik, 1985; Massagu6, 1985.
In contrast to EGF, TGFa'has been detected as early
as day 7 in mouse embryos using a specific radioimmunoassay procedure. The levels fall and then rise to
a second peak in day-13 fetuses (Twardzik, 1985), in
parallel with the levels of mRNA (Lee, Rochford,
Todaro & Villareal, 1985a). Later in development,
the placenta could be a major source of TGFQ(Stromberg etal. 1982). These studies imply that early
embryonic development could be affected by TGFabinding to EGF receptors, but the details of which
embryonic tissues synthesize the growth factor and
where TGFa'finds its target are still to be discovered.
(3) CSF-1 receptor/c-frns
The x-fms product is the transforming protein of
the McDonough strain of the feline sarcoma virus
(SM-FeSV). Its proto-oncogene homologue is a
membrane-inserted phosphorylated glycoprotein of
approximately 165 K in mouse and 170 K in cat. The
identity of the c-fms gene was first suggested by Sherr
et al. (1985) who showed that it is very similar if not
identical to the monocyte/macrophage cell surface
receptor for CSF-1. The c-fms gene product is a
tyrosine kinase, and the gene is therefore a member
of the src family of related oncogenes (Rettenmier,
Chen, Roussel & Sherr, 1985; Coussens et al. 1986).
The tissue expression of c-fms appears to be limited
to the monocyte/macrophage lineage (spleen, bone
marrow and fetal liver) and to developing extraembryonic tissues in mouse and human where it is
expressed in a stage- and tissue-specific manner
(Muller et al. 1983a). Highest levels of accumulated
transcripts are present in 17th-19th day placenta with
lower amounts in amnion, visceral yolk sac and
chorion. The question arises whether this expression
in extraembryonic tissues is due to high levels of
macrophages found there. This will only be answered
when in situ localizing methods are performed. However, evidence from a human teratocarcinoma cell
line indicates that c-fms may be specific to placental
cells. HT-H cells differentiate spontaneously in
monolayer cultures to trophoblast-like cells that secrete hCG a sub-units and that express c-fms mRNA
(Izhar et al. 1986). This phenotype is cell-type specific
since undifferentiated stem cells and other types of
cells that differentiate from HT-H cells in aggregates
do not express c-fms and do not secrete hCG. Be Wo
human choriocarcinoma cells also express c-fms,
further supporting localization in placental cells
(Muller et al. 1983a,6).
(4) c-src
The src proteins were the first tyrosine kinases to be
discovered and form the archetype for this group of
oncogene products, \-src encodes the transforming
protein of the avian Rous sarcoma virus and c-src
encodes a similar 60K protein. The demonstration
that protein kinases are involved in oncogenemediated transformation stems from the finding that
pp60"lc is tightly associated with a protein kinase
activity (Collett & Erikson, 1978; see review by
Oncogenes in development
Wyke, 1983). The Rous SV product also phosphorylates phosphatidylinositol and diacylglycerol (Sugimoto, Whitman, Cantley & Erikson, 1984), and
so its function is linked with other oncogene
products which also affect phospholipid metabolism.
A pp60VJnc related tyiosine kinase has been purified
from bovine brain cerebral cortex (Neer & Lok, 1985)
as a 61K protein that can be phosphorylated on serine
as well as tyrosine. It exhibits an autophosphorylating
activity and also phosphorylates precipitating antibody (Resh & Erikson, 1985). Its location is on the
cytoplasmic face of the cell as well as perinuclear. The
amino terminus of pp6ffrc is myristylated, and this is
needed both for localization to the inner face of the
plasma membrane and for cellular transformation
(Kamps, Buss & Sefton, 1985).
When the pp60v~jrc gene is transfected into NIH
3T3 cells, gap junction communication between adjacent cells is inhibited and the activity of protein
kinase C is enhanced (Chang et al. 1985). These
activities suggest that if c-src has a similar function, it
could be important to development. It was found
several years ago that chick embryonic neural tissues
express high levels of c-src (Cotton & Brugge, 1983).
Immunoassays show that most tissues have eight- to
ten-fold lower levels of c-src than brain, retina and
spinal ganglia. Immunocytochemical studies show
highest levels in neural tube, brain and heart of stage32 chicks, with lower levels in eye, limb bud and liver.
A similar distribution is found in human fetuses with
highest levels in cerebral cortex, spinal cord and heart
(Levy, Sorge, Meymandi & Maness, 1984; Gessler &
Barnekow, 1984). Thus the expression of c-src correlates strongly with the differentiation of electrogenic
tissues when proliferation has ceased and expression
persists in terminally differentiated neurones.
Recent immunocytochemical staining results of
Maness, Sorge & Fults (1986) show that developing
neural tissues in chick exhibit pp6O*rc expression at
two different stages. On or before stage 4, transient
localization is seen in the neural ectoderm. This
declines by stage 12 (45-49 h) and later rises again in
terminally differentiated neurones at about stage 21
(day 3-5) in the neural retina (Sorge, Levy & Maness,
1984) and stage 17 (day 2-5) in the cerebellum (Fults,
Towle, Lauder & Maness, 1985). Therefore it appears that c-src may play a role at proliferative stages
also. An analogous pattern of c-src expression in
Drosophila has been shown by in situ hybridization
(Simon, Drees, Kornberg & Bishop, 1985). c-src
mRNA is abundant in early embryos during gastrulation, low in larvae, and high in neural tissue and
smooth muscle and pupae at later stages.
In vitro culture systems have been used to elucidate
the location, effects and roles of c-src. Immunostaining shows that c-src is distributed all over cell bodies,
453
processes and growth cones of chick dorsal root
ganglion cultures (Maness, 1986). Primary cultures of
neurones or astrocytes from rat brain contain 15- to
20-fold more c-src protein than fibroblasts, and the
kinase specific-activity of c-src in neurones is 6- to 12fold higher than in astrocytes (Brugge et al. 1985).
Intriguingly, neuronal but not astrocytic c-src differs
in size by a post-translational modification in the
amino-terminal half. The murine teratocarcinoma
cell line, PCC7, can be induced to differentiate into
neuronal structures and a parallel elevation (3- to 5fold) in c-src mRNA can be detected (Sejersen,
Bjorklund, Sumegi & Ringertz, 1986). An 8- to 20fold increase in src protein levels is observed after 5
days of induction of P1951801A1 murine EC cells
with retinoic acid, corresponding to the appearance
of neuritic processes and other neuronal markers.
The induced src protein is the slower mobility form
associated with neurones, a finding that suggests the
usefulness of teratocarcinoma cell model systems
(Lynch, Brugge & Levine, 1986).
Studies with RSV infections or \-src introduced
into cultured cells have also given results that suggest
both proliferation and differentiation can be induced
by the gene. For instance, marrow cultures are
induced to greater selfrenewal of haematopoietic
progenitor cells (Boettiger, Anderson & Dexter,
1984), while retrovirus carrying \-src introduced into
PC12 rat phaeochromocytoma cells induces some
features characteristic of differentiation (neurite extension) (Alema, Casalbore, Agostini & Tato, 1985).
v-src-containing viruses suppress differentiation in
chondroblasts as measured by the synthesis of chondrocyte-specific products (Alema, Tato & Boettiger,
1985). However, \-src has different properties to c-src
and may also be regulated differently.
(5) c-abl
The Abelson leukemia virus (Ab-MLV) induces B
and T cell lymphomas in mice by means of the
expression of v-abl, which encodes a tyrosine kinase
of 160 K. Cooperation with EGF receptors appears to
be necessary for v-abl to transform murine fibroblasts
into tumorigenic cells (Gebhardt, Bell & Foulkes,
1986). An homologous c-abl of 150 K is found in
normal mouse cells (Goff, Gilboa, Witte & Baltimore, 1980). c-abl is actively transcribed during
embryo and fetal development with high levels of
transcripts in extraembryonic tissues as well as in the
fetus proper (Miiller et al. 1982). Its expression is
highest on day 10 when organogenesis is progressing
rapidly. Thereafter, mRNA levels fall during gestation but are detectable throughout. Low levels have
been detected in several teratocarcinoma cell lines
(Sejersen, Sumegi & Ringertz, 1985).
454
E. D. Adamson
(6) Other oncogene kinases
Very little is known about the expression of the other
tyrosine kinases in development. The proto-oncogene c-ros has features in common with the EGF
receptor family and displays tissue-specific and developmentally regulated expression (Neckameyer,
Shibuya, Hsu & Wang, 1986). The oncogene \-kit,
which is the transforming gene of HZ4 feline retrovirus, has homologous regions to PDGF receptor and
c-fms, but is presumably a truncated version with no
transmembrane domain (Besmer et al. 1986).
Distantly related to the tyrosine kinase encoding
oncogenes is v-raf, which has ser/thr kinase activity.
The c-raf-1 gene has been cloned and utilized to
evaluate expression in mouse embryos. mRNA is not
detected, while a related but distinct gene, A-raf, is
transcribed in 14-day embryos with less in 18-day
embryos and placenta. Moderate levels were found in
certain adult tissues (Huleihel et al. 1986).
The cellular homologue of the transforming gene
product, p2>lc'mos, of the Moloney murine sarcoma
virus (Papkoff, Nigg & Hunter, 1983) was thought to
be unexpressed in mouse tissues. By sensitive SI
nuclease and Northern assays, expression has been
detected in whole embryos at moderate levels, in
placenta, kidney and brain at very low levels, and at
high levels in adult testes and ovary. Transcript sizes
differ in different tissues and it was suggested that
tissue-specific regulation of the size of mos transcripts
could be transactivated, for example, by hormones,
and could give rise to functionally different protein
products (Propst & Vande Woude, 1985).
(7) The ras family of genes
The ras genes were first identified as the viral oncogenes of the Harvey and Kirsten rat sarcoma viruses
(Ellis, DeFeo, Furth & Scolnick, 1982). Cellular ras
genes have been identified in most species, and they
constitute a family of three human genes which
encode a remarkably well-conserved protein, designated p21 (Defeo et al. 1981). The p21 protein is
located on the cytoplasmic face of the plasma membrane in both normal and transformed cells. In vitro,
p21 binds GTP (Finkel, Der & Cooper, 1984), but the
normal gene product hydrolyses GTP at a rate 8- to
10-fold higher than that of the transforming protein
(Sweet et al. 1984). ras proteins are structurally and
functionally analogous to the G proteins which are
involved in adenylate cyclase regulation (Gilman,
1984; Hurley et al. 1984). The potential relationship
between adenylate cyclase and p21 may be part of the
control of cell division in Xenopus laevis oocytes.
Progesterone-induced meiotic activation of germinal
vesicle breakdown (GVBD) is mediated, at least in
part, by inhibition of the oocyte adenylate cyclase
(Finidori-Lepicard et al. 1981), but it appears not to
involve the inhibitory guanine-nucleotide binding
subunit G,. Sadler, Schechter, Tabin & Moller (1986)
showed that monoclonal antibodies to p21-ras inhibited adenylate cyclase activity and gave accelerated maturation of Xenopus laevis oocytes in a dosedependent manner. It is possible either that p21
protein interacts with the pathway of normal cell
division regulated by progesterone or that antibodies
cross react with the oocyte G proteins. Ras proteins
appear to interact with phospholipase C in a G
protein-like manner (Fleischman, Chahwala & Cantley, 1986), and c-Ki-ras-2a has some homology with
lipocortin and related proteins (Kretsinger & Creutz,
1986).
The ras gene products are clearly involved in an
important aspect of cell proliferation since even
normal p21c""" when expressed at elevated levels can
result in the immortalization and transformation of
mouse cells (but not human cells). c-Ha-ras and c-Kiras expression is detected at all stages of mouse
embryonic development at almost unvarying levels
(Miiller et al. 1982; Muller, 1983; Slamon & Cline,
1984). This would suggest a general metabolic role in
development, ras proteins are remarkably conserved
evolutionarily, with homologous proteins occurring
in yeast which have similar GTP-binding and hydrolytic properties (Temeles et al. 1985) and in
Drosophila (Mozer, Marlor, Parkhurst & Corces,
1985). Of the three v-Ha-ras-related cellular genes in
D. melanogaster, each is transcribed into two sizes of
mRNAs. The larger is expressed at similar abundance
during the life cycle stages, while the shorter transcript is more abundant in embryonic stages (Lev,
Kimchi, Hessel & Segev, 1985). In situ hybridization
was used to locate and identify active tissues. Distribution is uniform in embryos but is restricted to
dividing cells in larvae. However, in the adult, both
dividing and nondividing tissues contain high levels of
ras transcripts, including ovaries, cortex of brain and
ganglia, thus suggesting roles in growth and in differentiation (Segal & Shilo, 1986). An homologous p23
protein in Dictyostelium discoideum is expressed at
highest levels in growing organisms, and this declines
with the onset of differentiation (Pawson et al. 1985).
Similarly, F9 murine teratocarcinoma cells express
high levels of c-Ha-ras mRNA and this is moderately
diminished during differentiation (Campisi et al.
1984). However, c-Ki-ras expression increases after
48 h of stimulation of differentiation of mouse erythroleukemic cells with DMSO. Other oncogenes are
also induced, including fos, myb, and myc, while ten
others remain unchanged (Todokoro & Ikawa, 1986).
The differentiation inducing properties of c-Ha-ras
were tested by introducing sarcoma viruses carrying
Oncogenes in development
ras oncogenes into PC12 cells (Noda etal. 1985) or by
microinjecting purified normal or activated Ha-ras
proteins (Bar-Sagi & Feramisco, 1985). There is no
effect of normal c-ras on PC12 differentiation, but
activated Ha-ras products induce differentiation in
both cases. Antibody to p21-ras protein microinjected
into PC12 cells inhibits nerve-growth-factor-induced
differentiation (Hagag, Halegoua & Viola, 1986),
and this indicates that c-ras does indeed play a role in
differentiation.
The expression of c-Ki-ras appears to be cell cycle
dependent in a chemically transformed mouse fibroblast cell line with highest expression in mid to late
Go/Gi (Campisi etal. 1984). In addition, antibody to
ras microinjected into quiescent NIH 3T3 cells prior
to serum stimulation blocks a large population of cells
from entering S phase later while control antibodies
do not. A time course shows that c-ras activity is
needed just before S phase or about 8 h after addition
of serum (Mulcahy, Smith & Stacey, 1985). A similar
time of c-Ha-ras gene activation is found after partial
hepatectomy in rats, and this returns to normal after 3
days suggesting that proto-oncogene regulation is a
normal regulated process in non-neoplastic growth
processes (Goyette, Petropoulos, Shank & Fausto,
1984).
(8) c-fos
The FBJ and FBR murine osteosarcoma viruses
rapidly induce osteosarcomas in mice, and a 55 K
protein encoded by the transforming gene, v-fos, of
the FBJ virus (J5&a*-fos from FBR-MSV) has been
described (Curran & Teich, 1982; Curran & Verma,
1984). The cellular homologue, c-fos, also encodes a
55 K protein, which differs from the viral protein in
the carboxy-terminal portion, but which, nevertheless, can transform normal fibroblasts (Miller, Curran
6 Verma, 1984). Both proteins are nuclear phosphoproteins and both are turned over rapidly in the cell,
\-fos with a half life of 2 h and c-fos about 20 min. c-fos
protein differs in the degree of post-translational
modifications that can be detected soon after synthesis (Curran, Miller, Zokas & Verma, 1984). See
reviews by Miiller & Verma (1984) and Deschamps et
al. (1985) for further details.
(8.1) c-fos expression in developing tissues and
proliferating cells
A distinguishing feature of c-fos expression is that
although transcripts are present at barely detectable
levels in embryos and fetuses, the extraembryonic
tissues have very high levels (Miiller etal. 1982). Day7 murine conceptuses consisting predominantly of
extraembryonic tissues have very high levels of expression and, on further examination, a stage- and
455
tissue-specific pattern is detectable (Muller, Verma &
Adamson, 1983c). In the mouse, amnion >visceral
yolk sac > placenta, and a similar pattern is found in
human tissues (Muller etal. 19836). In the mouse the
level of c-fos mRNA rises to a plateau on the 16th to
17th day of gestation in extraembryonic tissues and
also 14th day (haematopoietic) fetal liver, and later
skin and bone/bone marrow contain high levels.
Fetal liver and bone marrow probably express c-fos
largely because of the population of macrophages and
other haematopoietic lineages that express c-fos
either constitutively or at some stage in their differentiation/maturation processes (Muller, Muller & Guilbert, 1984; Muller, Curran, Muller & Guilbert, 1985).
Macrophages cannot account for the high expression
in very early extraembryonic tissues. In situ localization of c-fos protein (Adamson, Meek & Edwards,
1984) and mRNA (Deschamps et al. 1985) has clearly
located fos expression in all the cells of the extraembryonic tissues. In addition, extraembryonic tissues
have been shown to synthesize p55c"^OJ protein
(Mason, Murphy & Hogan, 1985). Therefore, what is
the role of c-fos gene expression in these tissues?
A brief survey follows of the three types of stimuli
that induce c-fos expression, including growth, differentiation and stress stimuli. Quiescent, serum-starved
mouse or rat fibroblasts in Go, stimulated to 'competence to divide' by PDGF, FGF (or serum), activate the fos gene within a few minutes; mRNA levels
peak at 30 min and then fall to low levels in 60 min.
This is caused by an increased rate of transcription
and is accompanied by increased protein synthesis.
The increased levels of mRNA and protein synthesis
are both transient (Greenberg & Ziff, 1984; Muller,
Bravo, Burckhardt & Curran, 1984; Kruijer, Cooper,
Hunter & Verma, 1984; Treisman, 1985; Zullo, Cochran, Huang & Stiles, 1985; Renz et al. 1985; Greenberg, Hermanowski & Ziff, 1986). In all cases c-fos
mRNA accumulations are followed by an increase in
the level of c-myc mRNA, although it is not known if
these are linked responses. Epithelial and other cells
respond to their specific mitogens with a similar
transient increase in fos mRNA: EGF-stimulated
A431 cells (Bravo, Burckhardt, Curran & Muller,
1985); PC12 cells (Greenberg, Greene & Ziff, 1985);
and primary hepatocytes (Kruijer etal. 1986); thymocytes stimulated with concanavalin A (Moore, Todd,
Hesketh & Metcalf, 1986); thyroid cells with thyrotropin (Colletta, Cirafici & Vecchio, 1986; Tramontano, Chin, Moses & Ingbar, 1986); peripheral lymphocytes with phytohaemagglutinin and calcium
ionophore (Reed, Alpers, Nowell & Hoover, 1986).
Primary amnion cell cultures continue to express c-fos
protein for 2h after culture in vitro but this level
declines to zero in 15 h. Addition of undefined factors
in medium conditioned by placental or embryo
456
E. D. Adamson
explants stimulates the re-expression of fos protein
(Miiller et al. 1986). Apparently, constitutive expression of fos in amnion may be maintained by
stimulatory endogenous factors that are produced by
fetal and placental tissues. These examples suggest
that c-fos is transiently expressed whenever mitogens
bind to a cell receptor, but the following cases show
that the subsequent response of a cell is not necessarily correlated with cell division.
(8.2) c-fos induction associated with cell
differentiation
When PC12 cells are stimulated with nerve growth
factor (NGF), they sprout neurites and become
differentiated, non-dividing, neurone-like cells. The
c-fos gene is rapidly activated with similar kinetics as
when proliferation is stimulated with EGF or FGF
(Greenberg et al. 1985; Kruijer, Schubert & Verma,
1985; Milbrandt, 1986). In contrast, c-fos is not
activated when PC12 cells differentiate to chromaffln-like cells when treated with glucocorticoids
(Deschamps et al. 1985). In the case of PC12 cells,
c-myc is also activated, whereas in other differentiating systems c-myc mRNA levels usually fall preceding or accompanying falling levels of proliferation. Other cell types that express elevated c-fos
mRNA levels when stimulated to differentiate include HL-60 and U-937 human leukemia cells when
treated with the phorbol ester TPA (Mitchell, Zokas,
Schreiber & Verma, 1985; Miiller et al. 1985) and
WEHI-3B cells induced with granulocyte-colony
stimulating factor (Gonda & Metcalf, 1984). In the
latter case, c-fos mRNA accumulates to high levels
only after 2-3 days, when differentiation to monocytes occurs. In cell lines that differentiate to monocyte/macrophages,/as mRNA levels remain moderately high and therefore differ from growth factor
responses. The activation of c-fos appears to be
lineage-specific since HL-60 cells differentiating to
granulocytes do not activate fos (Miiller et al. 1985;
Mitchell et al. 1985). c-fos expression is constitutively
high in a mast cell precursor line (PB-3c) grown in the
presence of interleukin 3 (IL-3) (Conscience, Verrier
& Martin, 1986). When IL-3 is withdrawn, the c-fos
level falls and is rapidly induced when growth factor is
added back. This cell line and macrophages express
high levels of fos while actively proliferating as
differentiated cells. It cannot be concluded that
certain lineages of differentiation require fos activation, since an HL-60 cell line resistant to TPA can
be induced to differentiate to macrophages in the
absence of detectable c-fos mRNA expression (Mitchell, Henning-Chubb, Huberman & Verma, 1986).
Neither can it be concluded that fos is not required
since it is possible that a stable form of fos protein is
present.
(8.3) c-fos activation by other stimuli such as heat
shock
From the above examples, it can be seen that many
different external stimuli seem to activate the transient expression of c-fos mRNA. When quiescent
HeLa cells are changed from culture at 37 °C to 40 °C
to 44°C, a temperature-dependent, 5- to 20-fold
increase in c-fos mRNA and protein levels follows in
about lh (Andrews, Harding, Calbet & Adamson,
1987). Ionic signals such as calcium ionophore, benzodiazepines and elevated K + (Curran & Morgan,
1985; Morgan & Curran, 1986), the cell division
inhibitor mitomycin C and ultraviolet light (unpublished observations of S. Edwards and E. Adamson)
all induce c-fos mRNA expression. Partial hepatectomy and even a sham operation elevate c-fos
mRNA levels in rat liver (Kruijer et al. 1986).
Wounding a fibroblast monolayer results in rapid
induction of c-fos (Verrier, Miiller, Bravo & Miiller,
1986). /3-adrenergic stimulation of mice in vivo produces hyperplasia in parotid and submandibular salivary glands and stimulates transient c-fos expression
(Barka, Gubits & Vander Noen, 1986). In summary,
many kinds of external stimuli achieve a rapid cellular
response in the form of c-fos gene induction and
strongly suggests that fos is important in relaying
extracellular signals to the nucleus, but the mechanisms remain unknown.
(8.4) c-fos expression in teratocarcinoma model
systems of development
c-fos mRNA is expressed at very low levels in
proliferating EC cells (Miiller, 1983; Vilette,
Emanoil-Ravier, Tobaly & Peries, 1985; Edwards &
Adamson, 1986) and increases modestly during F9
aggregate differentiation to embryoid bodies, peaking on day 3 after retinoic acid addition (S. Edwards
and E. Adamson, unpublished data; Miiller, 1983).
P19 EC aggregates stimulated with DMSO to differentiate into a mixture of cell types, including cardiac
muscle express c-fos mRNA in increasing amounts
peaking on the 12th day (Edwards & Adamson,
1986). These results indicate that c-fos expression can
accompany teratocarcinoma cell differentiation and
support the findings of Miiller & Wagner (1984) and
Ruther, Wagner & Miiller (1985) who showed that
the integration and expression of normal exogenous
c-fos genes in F9 cells stimulates differentiation. P19
EC cells are less affected, however, and PC13 cells
are not stimulated to differentiate by c-fos expression.
Thus c-fos expression alone is not sufficient to trigger
differentiation. Apparently contrary to the hypothesis that c-fos expression may be necessary (but not
sufficient) for differentiation to occur, Mason et al.
(1985) did not find elevated c-fos mRNA levels during
F9 differentiation in monolayer cultures stimulated
Oncogenes in development
with retinoic acid and cAMP, but did detect a
transient slight induction 60min after RA addition.
An effective way to determine the function of a
gene is to introduce complementary RNA into cells
and determine the effect of the prevention of the
expression of the protein product of that gene. The
introduction of 'anti-sense' fos DNA into 3T3 cells
has already shown to be effective in reducing growth
rates and in reducing the frequency of such clones
(Holt, Gopal, Moulton & Nienhuis, 1986). Our
unpublished results indicate that anti-sense fos DNA
expressed in F9 EC cells inhibits their ability to
differentiate in response to RA. This experimental
approach together with antibody injections, will
likely become prominent in the near future. So far,
the data support a hypothesis that fos may be important to development in two ways: one, to act as the
'second messenger' for a variety of external stimuli
and second, to act in some part of the differentiation
process, perhaps a step that is connected with growth
restriction or with initiating a new programme of gene
regulation associated with differentiated function.
(9) c-myb
c-myb is the homologue of the viral transforming gene
in E26 and other avian viruses that produce myeloblastosis in birds, c-myb expression is restricted to,
and is developmentally regulated, in haematopoietic
tissue and is therefore thought to play a specific role
in haematopoiesis (Duprey & Boettiger, 1985). c-myb
is expressed in a differentiation stage-specific manner
in pre-B cells lines (DeCino, Herbst, Lernhardt &
Raschke, 1987). Five percent of the haematopoietic
cells of the chick yolk sac contain all the detectable
c-myb mRNA of that tissue. These cells were identified as M-CFC or the committed progenitors to the
macrophage lineage. As the cells differentiate, the
level of c-myb falls more than 100-fold. A similar fall
accompanies WEHI-3B cell differentiation to macrophages (Gonda & Metcalf, 1984). Proto-oncogene
c-myb expression is not restricted to macrophages
since both T cells in the murine thymus and cells of
the erythroid lineage also express c-myb, and this falls
tenfold with increasing age (Sheiness & Gardinier,
1984). In situ hybridization confirms these lineages
and demonstrates the presence of c-myb mRNA in
rapidly proliferating precursors of the myeloid and
erythroid lines in human bone marrow cells (Emilia et
al. 1986).
(10) The myc gene family
c-myc is the genomic counterpart of the transforming
gene of the avian myelocytomatosis virus (MC29)
457
and, like c-myb and c-fos, its protein product moves
rapidly to the nucleus after synthesis and is shortlived. Other homologous genes have been termed
L-myc and N-myc corresponding to their activity
detected in lung and neural tumours, respectively.
The examples of c-myc expression in response to
mitogens of many kinds have been listed in the
section on c-fos and include thrombin, with insulin
acting on Chinese hamster fibroblasts (Blanchard et
al. 1985). In contrast, there are some exceptions
where growth-stimulating factors do not induce c-myc
mRNA levels: insulin (Kelly, Cochran, Stiles &
Leder, 1983); B cell growth factor (Smeland et al.
1985), and adenovirus infection (Liu, Baserga &
Mercer, 1985). In spite of the large variations seen in
c-myc mRNA levels, its rate of transcription increases
only modestly when cells move from Go to Gi and
then remains at the same lower level in all phases of
the cell cycle (Thompson, Challoner, Neiman &
Groudine, 1985; Rabbitts et al. 1985; Kaczmarek,
1986) and differentiation (Dean, Levine & Campisi,
1986). Even more than for c-fos, post-transcriptional
regulation is the major means by which the level of
expression of c-myc is modulated. However, for
growth stimulation of fibroblast cells by growth factors, an elevated transcription rate can occur depending on the cell type and the growth factor.
(10.1) c-myc expression and cell proliferation
c-myc, until recently, has been well correlated to
various aspects of cell proliferative states (Birnie,
Burns, Clark & Warnock, 1984). In transgenic mice,
where levels of c-myc are elevated by introduction of
the c-myc proto-oncogene coupled to the immunoglobulin [i or K enhancer, frequent occurrence of
lymphomas occurs within a few months of birth
(Adams et al. 1985). Translocation of the c-myc gene
to a chromosomal location that endows altered expression has been found in many leukemias in mouse
and human. Although induction of the c-myc gene
occurs when erythroleukemic cells are stimulated to
differentiate, expression is transient and, in general,
low levels of c-myc are present in differentiating
haematopoietic cells (Gonda & Metcalf, 1984; Lachman & Skoultchi, 1984). In view of the association of
c-myc with proliferation, it is not easy to understand
why both mitotic and meiotic phases of germ cells
have very low levels of c-myc transcripts (Stewart,
Bellve & Leder, 1984). For somatic cells like
quiescent Swiss 3T3 fibroblasts, DNA synthesis is
stimulated by c-myc protein injected into the nuclei
(Kaczmarek et al. 1985). Here c-myc acts like a
competence growth factor to initiate the cell cycle so
that cells progress into S phase. It now appears that at
least one way that c-myc may act is by participating in
the process of DNA synthesis, since the addition of
458
E. D. Adamson
affinity-purified anti-c-myc antibodies to isolated nuclei from several types of human cells reversibly
inhibits DNA synthesis and DNA polymerase activity
of the nuclei (Studzinski, Brelvi, Feldman & Wall,
1986).
(10.2) c-myc in development
Not surprisingly, the c-myc gene is highly active
during development. Stage-specific expression of
c-myc mRNA was found by Pfeifer-Ohlsson et al.
(1984) in human placenta with 30-fold variation in
level. Four- to five-week placenta was the highest,
and this declines to much lower levels by the end of
the first trimester. The mRNA is located predominantly in the cytotrophoblast cells where [3H]thymidine labelling also shows these cells to be rapidly
dividing. The nondividing syncytiotrophoblast of the
term placenta has 40-fold lower levels. Interestingly,
not every cytotrophoblast cell contains c-myc transcripts, and it was suggested that a wave of mitotic
activity moving down the placental villi may correlate
with accumulated levels of c-myc mRNA. A most
relevant observation is that coexpression of c-sis and
c-myc occurs in the early placenta (Goustin et al.
1985). Since c-sis codes for a PDGF-like mitogen,
secretion of this activity into the medium of cultured
trophoblasts of first trimester placenta may not be
coincidental (see section 11).
The human fetus proper also displays stage- and
cell-specific expression of c-myc with highest levels in
the rapidly proliferating epithelial tissues. These high
levels are sustained throughout the first trimester in
contrast to declining levels in the placenta during the
second month of gestation. The distribution of c-myc
levels implies more than mere association with proliferation; in 3- to 4-week embryos, c-myc expression
is low, while in extraembryonic tissue c-myc mRNA
levels are high (Pfeifer-Ohlsson et al. 1985). Furthermore, predominantly normal development occurs in
transgenic mice that express varying levels of c-myc
(Leder et al. 1986).
During murine development, c-myc mRNA has
been observed at high levels throughout, but a related
gene, N-myc, is highly expressed at very early stages
(7-5 days of gestation) and continues at this level until
11-5 days when it declines thereafter (Jakobovits,
Schwab, Bishop & Martin, 1985). Zimmerman et al.
(1986) examined the expression of all three mycreiated genes in murine postnatal development and
observed that c-myc expression is present at all stages
and in all tissues, c-myc levels decline to low levels in
older adults in most tissues except adrenals, thymus,
spleen, intestine and heart. Tissue- and stage-specific
expression was demonstrated for L-myc and N-myc.
L-myc expression is highest in newborn forebrain,
hindbrain and kidney, at lower levels in lung and
intestine, and absent in other tissues. L-myc expression is still present in adult lung but decreases in
all other tissue so that a 17-day-old brain no longer
expresses L-myc. N-myc was thought to be neuroectoderm-specific but in fact is found in a variety of
newborn tissues. It is highest in newborn brain,
kidney and intestine, and declines rapidly with increasing age. In addition, a striking differential distribution is observed in various B cell lines. N-myc is
present in pre-B cells but not B cells or plasma cells,
while c-myc is expressed in all of these lines, and Lmyc is never expressed. Very high c-myc expression
occurs in late fetal mouse cerebellum that declines
and is succeeded by a second peak in postnatal days 3
to 10 (Ruppert, Goldwitz & Wille, 1986). The latter is
localized in the mitotically active external granular
layer and accompanies a change in the ratio of the two
myc mRNAs to adult ratios. In general, the expression of myc family genes correlates with committed but still proliferating cells as well as with cells that
are rapidly differentiating along the neural pathway.
The only non-neural tissue in which a relatively
high level of expression of N-myc and c-myc is
observed is fetal and newborn kidney. If the myc
family genes can all be stimulated by growth factors,
possibly either the production and activity of preproEGF accounts for myc activation, or more likely, the
constant exposure of the kidney to blood-borne
growth factors stimulates high levels of expression of
these oncogenes. N-myc is also expressed in mouse
and human teratocarcinoma stem cells and in adult
mouse testis (Tainsky, Cooper, Giovanella & Vande
Woude, 1985; Jakobovits et al. 1985).
The myc gene is highly conserved through evolution and even Drosophila melanogaster genome contains sequences that hybridize with the v-myc probe,
although there is little amino acid sequence homology
in the products. Nevertheless, hybridizing transcripts
are found in embryos, pupae, adults and in a Drosophila cell line (Kc), and stage-specific expression of
several different-sized transcripts were recorded. The
results also suggest that the transcripts found in early
embryos are of maternal origin since they are found
only in the ovaries (Madhavan, Bilodeau-Wentworth
& Wadsworth, 1985).
(10.3) c-myc expression in teratocarcinoma cells
The steady-state levels of c-myc found in proliferating
cells have been shown to decrease drastically (Dony,
Kessel & Gruss, 1985) in F9 EC cells at a stage even
preceding overt differentiation induced by retinoic
acid 72 h later (Griep & DeLuca, 1986). Post-transcriptional mechanisms are apparently wholly responsible for reduced c-myc mRNA levels in F9 cells. In
F9 cells stimulated to differentiate, the steady state of
c-myc is reduced by as much as 50 % within 3 h (Griep
Oncogenes in development
& DeLuca, 1986). However, if F9 cells are blocked
from differentiating in response to RA by the addition of 5 mM-sodium butyrate to the medium
(Levine, Campisi, Wang & Gudas, 1984) the cells still
respond to RA by decreased levels of c-myc. It
appears that reduced levels of c-myc are not sufficient
for differentiation but may precede differentiation or
reduced growth rates. The undermethylation of the
c-myc gene in F9 EC cells relative to differentiated
teratocarcinoma cells and mouse liver DNA may
account for its high level of expression and for its
regulation (Griep & DeLuca, 1986). The second exon
of the c-myc gene becomes methylated during F9
differentiation and this is remarkable in the face of
global demethylation of every other gene tested
(Young & Tilghman, 1984; Razin et al. 1984).
(11) c-sls
The predicted sequence of p28v~J", the transforming
protein of the simian sarcoma virus (SSV), is strikingly homologous to the B chain of PDGF (Waterfield et al. 1983; Robbins et al. 1983; Chiu et al. 1984)
or PDGF-2 (Rao et al. 1986). In SSV-transformed
cells, p28VJ" is proteolytically processed to generate a
disulphide-linked dimer (Johnson, Betsholtz, Heldin
& Westermark, 1986), and its presence and activity in
the culture medium can be detected and neutralized
by antibodies to PDGF. Using \-sis probes, transcripts of c-sis have been detected in many cell lines,
tumours and tissues (Eva etal. 1982). Transformation
of cells by a wide range of oncogenic agents appears
to activate a cellular gene encoding a PDGF-like
molecule and the induced expression of the c-sis gene
by TGF/3 has been suggested as the intermediary step
in the transformed phenotype induced by TGF/3
(Leof, Proper, Getz & Moses, 1986). Mouse embryo
fibroblast cells stimulated with TGF/J express activated the c-sis gene after 4 h with a peak at 12-16 h
and release a PDGF-like activity into the culture
medium, c-fos is also induced maximally at 4h with
the appearance of PDGF activity, while c-myc
mRNA levels peak at 8-12 h suggesting that PDGF
may have activated both genes. Since TGF/? is present in most normal tissues (Roberts et al. 1981) and
also in the placenta, serum (Stromberg & Twardzik,
1985) and blood platelets (Assoian et al. 1983), it is
possible that fetal growth may be modulated, at least
locally, by the release of TGF£ and PDGF.
(11.1) c-sis in development
The developmental^ regulated expression of the c-sis
gene has been mentioned in section 10 since c-myc
and c-sis expression occur together in the highly
proliferative cytotrophoblast cells of the first trimester cytotrophoblast shell. What is interesting about
459
this study (Goustin et al. 1985) is that placental
explants secrete a PDGF-like activity into the medium in a similar developmental time course. In
addition, cytotrophoblast-like cell lines established
from early placentae display PDGF receptors with
similar affinity for PDGF as fibroblast cells. These
cells also respond to PDGF by tenfold elevation of
c-myc mRNA levels in 2 h and by increased synthesis
of c-myc protein (several-fold stimulation within 7h).
Autocrine stimulation of cytotrophoblast cells by the
c-sis product that then results in c-myc and c-fos
expression is an attractive hypothesis. However, the
placenta produces a number of other growth factors
such as IGFs, FGF and TGF/3, and these could also
contribute.
PDGF is thought to mediate the proliferation of
smooth muscle cells in injured arteries and may be
involved in the pathogenesis of atherosclerosis.
Although in injury, the main source of PDGF is the
platelet, other cell types produce PDGF-like activity.
For instance, rat aortic smooth muscle cells isolated
from 13- to 18-day-old rat pups secrete a PDGF
activity into the medium, and could account for
autocrine stimulation of growth of these cells in
culture. This activity is developmentally controlled
since the same cell type isolated from adult rats does
not secrete PDGF (Seifert, Schwartz & Bowen-Pope,
1984). c-sis transcripts have been detected at moderate levels in cultured human and bovine endothelial
cells, at low levels in in vivo endothelium from human
umbilical vein and at very low levels in bovine aortic
endothelium in vivo (Barrett et al. 1984). These
results also suggest that the sis gene is activated in
certain cell types when removed from in vivo to in
vitro conditions.
Model systems using murine EC cells have suggested that early embryonic stem cells may produce a
PDGF-like activity (Gudas, Singh & Stiles, 1983;
Rizzino & Bowen-Pope, 1985) but fail to bind this
growth factor. It has not been definitively determined
if these cells lack PDGF receptors, or if they are
wholly down-regulated by the secreted PDGF. However, when F9, PC13 and PSA1 cells differentiate,
they form cell types that are able to bind and respond
to PDGF. If the corresponding embryonic cells,
namely early embryonic ectoderm cells, produce
PDGF-like factors, these could then stimulate the
growth of the adjacent, more differentiated cell
types, such as mesoderm cells which arise on the 7th
day of gestation in mouse. PDGF also has a potent
chemoattractant activity that stimulates the motility
of certain types of cells and this could play a role in
the migration of embryonic cells. Embryonic ectoderm cells could also produce other growth factors
shown to be secreted by EC cells (Rizzino, 1982;
Heath, Mahadevan & Foulkes, 1986).
460
E. D. Adamson
(12) Other proto-oncogenes
The latest of the viral oncogenes to be identified with
a cellular protein is v-erb-A, which has 89% homology to the thyroid hormone (T3) receptor (Weinberger et al. 1986). Thyroid hormone is known to be
essential for tadpole metamorphosis and the switch to
adult-type gene activities (Knowland, 1984). This
receptor occurs widely in mammalian tissues but
plays important roles in the liver and brain (reviewed
by Oppenheimer, 1979). The receptors have higher
affinity for T3 than T4, exist in two molecular forms
(Casanova et al. 1984) and appear to be largely
nuclear (Erkenbrack & Rosenberg, 1986). Since thyroid hormone is synthesized throughout gestation,
presumably the receptor is also an early product in
development.
The c-erb-A gene is related (22 % at the amino acid
level) to the glucocorticoid receptor (Weinberger et
al. 1985; Hollenberg et al. 1985) which is also partly
nuclear and partly cytoplasmic. The glucocorticoid
receptor is expressed in many cell types and is active
during embryogenesis in fetal liver, visceral yolk sac
(G. Andrews, personal communication) and the secondary palate (Diewart & Pratt, 1981; Kim, Lauder,
Joh & Pratt, 1984).
Two proto-oncogenes originally identified as
mouse genomic sequences adjacent to integrated
proviruses of the mouse mammary tumour virus
(MMTV) in a large proportion of tumours in mice,
int-1 and int-2 are unrelated genes, int-2 is transcribed
in embryos from day 8-5 to 12-5 and also is seen in
adult testis but not other adult tissues (Jakobovits,
Shackleford, Varmus & Martin, 1986). This limited
distribution should be helpful in determining the
function of the int gene.
(13) Proto-oncogene expression in
teratocarcinoma cells
Insufficient data have been accumulated to evaluate
teratocarcinoma cells as model systems for studying
proto-oncogene mechanisms in growth and differentiation, but the potential is great since the stem cells
may be engineered to express experimentally introduced genes. The effect on the stem cell and on the
pattern of differentiation produced should be highly
instructive. The studies of Muller & Wagner (1984)
and Ruther et al. (1985) have clearly suggested a role
for c-fos in differentiation, for example. Once an EC
cell line has been established that can express individual oncogenes, the cells may be aggregated with
normal embryonic cells at the morula stage, or
microinjected at the blastocyst stage, to follow its
effect on the development of the resulting chimaeric
animals. The proportion of engineered cells in each
tissue of the chimaera will vary in individual animals
and may allow a titration of dose versus effect.
To date, Table 2 summarizes what we know of the
levels of oncogene expression in teratocarcinoma
cells as transcripts that hybridize with DNA probes.
As expected, the oncogenes most closely associated
with proliferation are strongly expressed: these include c-src, c-abl, c-rasHa, c-ras1^, c-myc, and N-myc.
When rates of proliferation decline as differentiation
occurs, several oncogenes decline in mRNA level:
c-abl and c-ras decline modestly; c-myc and N-myc
decline drastically. Neuronal differentiation is accompanied by significant increases in c-src (Sejersen
et al. 1985; Lynch et al. 1986), but N-myc activity
decreases to low levels (Sejersen et al. 1986). The
nuclear oncogene, c-fos, is expressed transiently at
some point during differentiation that may indicate a
role in some general step of that process (Edwards &
Adamson, 1986).
Some studies have centred on introducing viral or
activated oncogenes into cell lines to observe effects
on cell phenotype and differentiation. For instance,
an activated ras gene, c-ras^3, introduced into P19 EC
cells appears to have little or no effect and does not
prevent the induction of differentiation in response to
retinoic acid (Bell, Jardine & McBurney, 1986).
However, viruses expressing v-fos (especially FBJMSV) are able to immortalize or transform mouse
embryo-derived primary cell cultures of fibroblasts,
myoblasts, and other cell types (Jenuwein, Muller,
Curran & Muller, 1985), thus linking \-fos expression
with increased growth potential in embryonic cells.
Since c-fos can also transform established cell lines
under the right conditions (Miller et al. 1984), the
distinction, if any, between the properties of v-fos and
c-fos proteins is not clear. The specific cell type
expressing the c-fos protein may modulate the outcome. The specific processed forms of oncogene
products such as c-fos, c-src and c-erb-A may differ
among tissues and may give rise to differences in
function.
(14) Conclusions
For most oncogenes, a specific function or activity has
not been assigned, and data are still too sparse to
hypothesize a mechanism in oncogenesis or to predict
a role in development. In the cases of c-erb-B/EGF
receptor, c-fms/CSF-1 receptor, c-sis/PDGF, an
obvious niche in growth regulation can be deduced.
Although these components are not direct gene
regulatory molecules, they do have wide-ranging
effects through their interconnections with a family of
protein kinases and through their effects on phosphoinositide metabolism, ion fluxes and nutrient
Oncogenes in development
461
Table 2. Expression o/c-oncs in teratocarcinoma cells
c-onc
CeU line
Exp" in ECC
c-erb-B/
EGF-R
F9, PC13
OC15
Intracellular
autophos. acty
Exp" in
differentiated cells
+
++
Reference
Reese/ al. 1979;
Adamson & Hogan, 1984;
Welter er al. 1987.
P19
-
+
c-fms
HT-H
-
trophoblast-like
cells +
Izhar er al. 1986.
c-src
PCC7
+
3—5x inc. during
neuronal diff '
Sejersen er al. 1985.
F9
P1951801A1
+
-
Sejersen er al. 1985.
+++
change in mobility
c-mos
c-fes
c-myb
c-erb-A
Mummery er al. 1985.
Lynch er al. 1986.
PC13, F9, 3TDM
PYS-2, PSA5E, C110
-
-
Sejersen ex al. 1985.
c-abl
PC13, F9, 3TDM
PYS-2, PSA5E, C110
low
low
Sejersen er al. 1985.
OC15, F9, HR9
c-ras
PC13, F9, 3TDM
PYS-2, PSA5E, C110
PCC4
+
++
+
+
+ + + gene
lower
Muller, 1983.
Sejersen er al. 1985.
Vilette er al. 1985.
amplified
c-myc
N-myc
c-fos
c-sis/PDGFlike factor
PC13, F9, 3TDM
PYS-2, PSA5E, C110
+
-
Sejersen er al. 1985.
F9
++
Post-transcriptional
down-regulation within
24 h of induction
of differentiation
Dony era/. 1985;
Sejersen er al. 1986.
human ECC
mouse ECC
++
PCC7, PCC3,
PCC4, F9
++
F9, OC15
low
low
F9
low
5x inc. by day 3 with
RA. Aggregates
F9
low
No inc. with RA &
cAMP. Monolayers
P19
low
20 x inc. by day 12 with
DMSO. Aggregates
PCC4
+
lower
PCC3 etc.
F9, PC13
low
low
low
-
int-1
F9, PSA
int-2
F9, PSA
Jakobovitz er al. 1985.
85 % reduction during
nerve differentiation
Sejersen er al. 1986.
Muller, 1983.
Edwards & Adamson
(unpublished data)
Mason er al. 1985.
Edwards & Adamson,
1986.
Vilette era/. 1985.
Sejersen er al. 1985.
Gudas er al. 1983;
Rizzino & Bowen-Pope,
1985.
Jakobovits ef al. 1986.
low
Footnotes: RA = retinoic acid; cAMP = dibutyryl cyclic AMP; DMSO = dimethyl sulphoxide.
transport. Nevertheless, the role of these growthrelated proteins is poorly understood. Largely this is
due to their complicated interconnections with many
cellular metabolic processes. Indeed, with a few
exceptions such as PDGF, the oncogenes seem to be
largely concerned with general metabolic processes as
much as (if not more than) growth regulation per se.
The proto-oncogenes that are known to have enzymatic activity, such as c-src, c-abl, the ras family, also
fit into this metabolic framework. c-erb-A/thyroid
hormone receptor is even more directly concerned
with overall metabolic rates.
462
E. D. Adamson
The nuclear-located proto-oncogenes are better
placed for roles in growth/differentiation/gene regulation. They bind to DNA to various degrees,
although specific binding sites have not been identified. The c-fos protein appears to bind to chromatin,
particularly at deoxyribonuclease I-sensitive sites,
thus indicating a role in the regulation of gene
expression (Sambucetti & Curran, 1986; Renz,
Verrier, Kurz & Muller, 1987). c-myc production is
similarly activated but usually at a slightly later time.
This has given rise to the possibility of chains of
command leading to gene-stimulating events generated by signals from the environment, c-fos and c-myc
may then activate sets of genes that lead to DNA
synthesis and progression through the cell cycle, or to
sets of genes that regulate differential cell-lineage
pathways.
TGF0
I
PDGF-—PDGF-R—-c-fos-"C-myc—Tas
TPA-
EGF
TGFa-
•*.
proliferation
J
differentiation
pK-C—*-c-fos-~-c-myc-~-c-fms
-EGF-R—-c-fos-^c-myc—»•
ras
In reviewing the data here it becomes clear that
almost without exception, the proto-oncogenes have
been shown to play roles in differentiation as well
as proliferation. Is this because directing the cell
towards proliferation limits the cell's resources to
continue the previous commitment or direction
towards a differentiated phenotype (e.g. c-mycl). Or
is it a more direct process that facilitates a differentiative pathway (e.g. c-fos?). Only in one case is the
function clear, that is, c-fms and this product appears
late and may only be a marker and not a regulator of
differentiation.
For considerations of the roles of proto-oncogenes
in development, some specificity of action may reside
in c-src since a neurone-specific isotype has been
identified in brain during proliferation, commitment
and expression of the neuronal phenotype. Other
proto-oncogenes are less well defined to specific
tissues. The placenta and other extraembryonic tissues (VYS, amnion, and chorion), however, do hold
a special place in the high levels of expression of
several c-oncs. In addition to c-myc, c-abl, c-ras, and
c-src, very high levels of c-sis, c-fos, and c-fms occur,
and these levels vary between the tissues mentioned
and between the temporal stages of the gestational
period. This makes it less likely that the undermethylated state of the DNA in these tissues (Rossant,
Sanford, Chapman & Andrews, 1986) broadly dictates the levels of proto-oncogene expression. It is
still possible that specific sites of methylated bases
control the expression of these or other genes in a
temporal and tissue-specific manner. The undermethylated state of the placenta could be necessary for the
derepression of a wide range of growth-related genes
that are known to be active in the placenta. In the
presence of secreted 'autocrine' growth factors such
as TGFa", TGF0, PDGF, IGF-I, and IGF-II, receptors are continually down-regulated, synthesized and
activating the chain of command. Although these
tissues have been recognized as 'pseudomalignant,'
they are not tumorigenic in nude mice and have
somehow controlled the signal to proliferate in parallel to the needs of the growing fetus. Studies on
modes of oncogene activation in carcinogenesis show
that a quantitative change of expression is one mechanism of such activation (reviewed by Klein & Klein,
1984). Understanding the mechanisms of control in
the placenta may therefore be instructive for future
clinical applications (Conway, 1983).
Limitations of space did not allow recognition of all
relevant references; for these omissions my apologies are
offered. I am grateful to Drs C. Van Beveren, C. Der, and
S. Edwards for comments on the manuscript. This work was
supported by grants CA 28424, P30 CA 30199 and HD
21957 from the National Institutes of Health.
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