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Oncogene (2000) 19, 2468 ± 2473
2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00
www.nature.com/onc
The role of STATs in transcriptional control and their impact on cellular
function
Jacqueline Bromberg1 and James E Darnell Jr*,1
1
Laboratory of Molecular Cell Biology, Rockefeller University, New York, NY 10021, USA
The STAT proteins (Signal Transducers and Activators
of Transcription), were identi®ed in the last decade as
transcription factors which were critical in mediating
virtually all cytokine driven signaling. These proteins are
latent in the cytoplasm and become activated through
tyrosine phosphorylation which typically occurs through
cytokine receptor associated kinases (JAKs) or growth
factor receptor tyrosine kinases. Recently a number of
non-receptor tyrosine kinases (for example src and abl)
have been found to cause STAT phosphorylation.
Phosphorylated STATs form homo- or hetero-dimers,
enter the nucleus and working coordinately with other
transcriptional co-activators or transcription factors lead
to increased transcriptional initiation. In normal cells
and in animals, ligand dependent activation of the
STATs is a transient process, lasting for several minutes
to several hours. In contrast, in many cancerous cell lines
and tumors, where growth factor dysregulation is
frequently at the heart of cellular transformation, the
STAT proteins (in particular Stats 1, 3 and 5) are
persistently tyrosine phosphorylated or activated. The
importance of STAT activation to growth control in
experiments using anti-sense molecules or dominant
negative STAT protein encoding constructs performed
in cell lines or studies in animals lacking speci®c STATs
strongly indicate that STATs play an important role in
controlling cell cycle progression and apoptosis. Stat1
plays an important role in growth arrest, in promoting
apoptosis and is implicated as a tumor suppressor; while
Stats 3 and 5 are involved in promoting cell cycle
progression and cellular transformation and preventing
apoptosis. Many questions remain including: (1) a better
understanding of how the STAT proteins through
association with other factors increase transcription
initiation; (2) a more complete de®nition of the sets of
genes which are activated by di€erent STATs and (3)
how these sets of activated genes di€er as a function of
cell type. Finally, in the context of many cancers, where
STATs are frequently persistently activated, an understanding of the mechanisms leading to their constitutive
activation and de®ning the potential importance of
persistent STAT activation in human tumorigenesis
remains. Oncogene (2000) 19, 2468 ± 2473.
Keywords: STAT; growth control; cancer; transcription; signal transduction
Introduction
Within a few years of the discovery in 1955 of
interferon (Isaacs and Lindenmann, 1957), the ®rst
*Correspondence: JE Darnell Jr
`cytokine' to be discovered, the growth restraining
properties of interferon preparations had been recognized (Baron et al., 1992; Paucker et al., 1962; Sokawa
et al., 1977). An avalanche of studies on what proved
to be a series of secreted small proteins followed in the
1960's and 1970's. The major basis for recognition and
de®nition of these extracellular factors was their ability
to induce di€erentiation and progression to maturity of
di€erent speci®c blood cell precursors (Metcalf, 1989).
Growth regulation as viewed in the 1990's context, i.e.
controlling crucial molecular events in the cell cycle
was, of course, not possible in the early stages of
cytokine studies, but the e€ects of cytokines on overall
cell growth were also important in their original
recognition. For example, IL-2 was discovered and
eventually puri®ed as a substance that allowed the
establishment of T cells in continuous culture (Arya
and Gallo, 1985; Arya et al., 1984), the basic breakthrough that allowed recognition of the AIDS virus.
Among the early results relating cytokines directly to
growth control was the demonstration that interferon
slowed the entry of cultured cells from late G1 into the
S phase and thus slowed cell growth rates (Balkwill
and Taylor-Papadimitriou, 1978; Baron et al., 1992;
Lin et al., 1986).
The molecular dissection of pathways through
which extracellular cytokines act on intracellular
molecules succeeded in the 1980's and early 1990's
®rst by identifying cytokine receptors and then
through molecular cloning obtaining their amino acid
sequences (Ihle 1995; Kishimoto et al., 1994). Second,
the genes were cloned for intracellular proteins
through which signals are passed from the liganded
receptor to the cell nucleus. These transcription
factors change cell behavior through transcriptional
regulation. The ®rst such pathway to be unearthed in
detail was IFN signaling through receptor associated
JAK tyrosine kinases to the latent cytoplasmic
transcription factors eventually termed STATs, for
signal transducers and activators of transcription
(Darnell, 1997; Darnell et al., 1994; Stark et al.,
1998). The tyrosine phosphorylated STATs dimerize
and accumulate in the nucleus where occupation of
speci®c DNA binding sites results in increased
transcription. Inevitably the role in growth control
of the STAT molecules, now numbering seven
identi®ed proteins (Stats 1, 2, 3, 4, 5A, 5B and 6)
activated by more than 40 di€erent polypeptides
became a central issue in cytokine research. In fact,
since the discovery of the STATs as targets of
cytokine activation, it was recognized in 1993 that
the STATs can also be activated in response to
`growth factors' such as EGF and PDGF and other
related ligands through the intrinsic tyrosine kinases
of the cognate receptors. Most recently still other
STAT proteins and growth control
J Bromberg and JE Darnell Jr
routes of STAT activation have been reported such as
G-protein signaling and angiotensin binding to its 7transmembrane receptor probably through Jak kinase
activation (Marrero et al., 1995; Vila-Coro et al.,
1999; Wong and Fish, 1998).
While this report will concentrate on the role of
Stat1 and Stat3 in growth regulation, it will be
useful ®rst to summarize the functional molecular
anatomy of the STATs and their interaction with
other proteins as they function in transcriptional
control (Figure 1a,b). It is generally assumed that
the biologic e€ects of the STATs depend on the
genes acted upon by these activated transcription
factors.
2469
The complexity of eukaryotic transcriptional initiation
and its regulation
Recent advances in the transcription ®eld have
occurred across a broad front implicating over 100
proteins that serve in recruiting polymerase II to a
start site (Gu et al., 1999; Holstege and Young, 1999).
A review of this vast subject is not possible here. But
we note simply that the multi-subunit polymerase II is
accompanied at a start site by a regular set of general
transcription factors (GTFs), and that initiation sites
in chromatin covered templates must, probably in
most cases, be exposed by chromatin remodeling
factors including histone acetyl transferases (HATs).
a
b
Figure 1 (a) Crystal structure of an N and C-terminally truncated Stat1 molecule bound to DNA. The structure of truncated Stat3
is virtually superimposable with that of Stat1 (Chen et al., 1998). (b) Functional domains of STAT proteins
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STAT proteins and growth control
J Bromberg and JE Darnell Jr
2470
Finally the activating proteins like the STATs
probably most often bind not alone, but in combination with other site speci®c and more general DNA
binding proteins in coordinated groups of proteins
termed enhanceosomes (Carey, 1998). The activating
proteins in the enhanceosomes are crucial to e€ect
changes in the rates of initiation and they do this by
acting through still other sets of proteins called coactivators of which a complex termed mediator (Gu et
al., 1999; Holstege and Young, 1999) may be the most
often used class but which also include the TATA box
binding factor TBP and the TBP associated factors,
the TAFs (Berk, 1999).
The positive acting proteins in an enhanceosome,
working coordinately, interact with the co-activators
and the chromatin remodeling proteins to cause
increased transcriptional initiation. One important
current area of research with the STATs is to discern
the parts of the STATs that interact with either (and/
or) other transcription factors or the various newly
discovered protein complexes to trigger transcription
initiation. Interaction sites between STATs and these
other proteins can then be tested for functional
requirements in transfection experiments in vivo and
they can ultimately be tested in vitro.
STAT domains: structure and function
From the three-dimensional structure of DNA bound
dimers of the core of Stats 1 and 3, several regular
domains of the proteins are obvious (Figure 1a,b).
Beginning around residue 130 there are four long
helical coils in which interactions with other proteins
occur. Residues *300 ± 500 comprise the DNA
binding domain, a region of beta-sheet structures
connected by unstructured loops. A linker domain
from *500 ± 575 that is all alpha helical followed by a
classical 7SH2 domain. Reciprocal pY-SH2 interactions hold the dimer together so that DNA contacts
on the dyad symmetrical binding site can occur.
(Missing from the core structure is the amino terminal
domain and the 7COOH terminal domain.) The
regions that have been implicated in transcription
activation are the 7COOH terminal 38 amino acids
of Stat1 and the terminal *75 amino acids of Stat3.
Included in the COOH terminal region of Stats 1 and
3 is a critical S (727 in both proteins) and a critical L
residue (724 in Stat1) (Wen et al., 1995; Zhang et al.,
1998). Interaction of this 7COOH terminal region
from both Stat1 and 2 with histone transacetylases has
been established (Bhattacharya et al., 1996; Horvai et
al., 1997; Zhang et al., 1996). In addition, and
dependent on serine phosphorylation, the Stat1
7COOH terminus interacts with MCM proteins
(Zhang et al., 1998). The MCM proteins are known
to be important in initiating DNA replication origins,
but their role in RNA synthesis is unknown. While all
of the STAT molecules depend on this 7COOH
terminal segment for transcriptional activation, other
regions of the STAT molecule also contribute to
transcriptional activation. The NH2 terminus is
required in transcription as judged by defective
stimulation in transfection experiments of NH2
terminal deletions (Meraz et al., 1996). Also there is
known interaction with histone transacetylases (CBP/
p300 proteins) by the 7NH2 terminal end of Stat1
Oncogene
which may contribute to transcription activation
(Horvai et al., 1997; Zhang et al., 1996). In addition
many natural STAT binding sites (and in fact the
most frequently used transfection target) contain
closely spaced tandem STAT binding sites (Darnell,
1997; Guyer et al., 1995). When two such sites are
occupied there is STAT dimer ± dimer interaction
mediated by the N-terminus (Vinkemeier et al.,
1998) (Xu et al., 1996) and this has proved to be
necessary for maximal transcriptional stimulation,
especially clearly for Stat5 (John et al., 1999).
Finally, mutations in the linker domain of Stat1
(connecting the DNA binding domain with the 7SH2
domain) led to a protein that can be phosphorylated
on tyrosine, dimerize, accumulate in the nucleus and
bind DNA but fail completely to activate transcription
(Yang et al., 1999).
In addition to these studies which presumably give
hints about how STATs themselves engage the
transcriptional machinery, there is considerable evidence of STAT interactions with other transcription
factors bound to neighboring sites in upstream
segments of the DNA of various genes. Thus, Stat1
and Sp1 interact on the ICAM promoter (Look et
al., 1995), Stat5 and the glucocorticoid receptor
interact on the b casein promoter (Stocklin et al.,
1996), Stat5 and CEBP on the immunoglobulin heavy
chain germline epsilon promoter (Delphin and
Stavnezer, 1995), Stat3 and c-Jun interact on the a2
macroglobulin promoter (Zhang et al., 1999) and a
host of other genes have been found to have closely
spaced required DNA binding sites for a STAT
protein and some other transcription factor (Guyer et
al., 1995; Look et al., 1995; Xu et al., 1996). These
enhancesome interactions in the STAT family of
proteins promise to be of great importance as they
are known to be in b IFN promoter (Kim and
Maniatis, 1997; Thanos and Maniatis, 1995) and in
the promoter for the alpha chain of T cell receptor
(Giese et al., 1995).
Against this brief background on the structurefunction relationship of STAT domains we now want
to consider the biologic roles of the STATs in growth
control.
Stat1 in growth restraint
The slower growth of cultured cells after IFN
treatment was established many years ago (Einat et
al., 1985a,b) and depends upon fully transcriptionally
activated Stat1 (Bromberg et al., 1996). Recently Stat1
null mice have added immense support for a growth
restraining role of Stat1 in the whole animal (Durbin
et al., 1996; Meraz et al., 1996). First, Stat17/7
animals develop tumors in response to lower doses
of methylcholanthrene treatment than do normal mice
(Kaplan et al., 1998). Furthermore, coupling the
Stat17/7 genotype with removal of the tumor
suppressor gene, p53, leads to greatly enhanced
spontaneous mouse tumor formation. Finally, the
cells in a number of human tumor samples show a
defective response in activation of Stat1 by IFN-g and
fail to slow growth in culture as a result. Thus it
appears that an IFN-g mediated Stat1 dependent
tumor surveillance system is at work in mice. Tumor
occurrence is suppressed by this system and estab-
STAT proteins and growth control
J Bromberg and JE Darnell Jr
lished tumors can escape suppression by avoiding the
growth restraint imposed by IFN-g.
Further results about growth restraint due to Stat1
have been described. In mutant chondroblasts, where
the FGF receptor is constitutively activated, persistent
activation of Stat1 is observed and profound growth
arrest associated with the activation of the Cdk
inhibitor, p21 (Sahni et al., 1999; Su et al., 1997).
Furthermore, in A431 cells, growth inhibition by EGF
correlates with Stat1 but not Stat3 activation (Bromberg et al., 1998a). Thus, there is mounting evidence
that Stat1 activation frequently provides an antiproliferative e€ect and may partially explain why the lack
of this molecule in vivo leads to increased tumor
formation.
Tumor formation may of course require a constant
growth stimulus but also cells that are accumulating
mutations, as is typical of cancer cells, must also escape
apoptosis. Stat1 in a number of cell types of this kind
promotes apoptosis (Chin et al., 1997; Kumar et al.,
1997) and its removal could also promote tumor cell
survival and establishment of tumors.
Possible roles of Stats 3 and 5 in human oncogenesis
For several years reports have accumulated showing
clinical tumor samples contain activated Stat 3 and 5
proteins without known ligand stimulation. Some of
the best studied cases in this connection is persistent
Stat3 activation in squamous cell head and neck
cancer (discussed by J Grandis in this volume) and in
multiple myeloma (discussed by R Jove in this
volume). The basis for constitutive activation of Stat3
in the case of squamous cell carcinoma is due to
aberrant EGF signaling. However in most of the other
clinically reported cases of persistent activation of
Stat3 the cause is not known.
In cell culture Stat3 was shown to be persistently
activated (tyrosine phosphorylated; and capable of
binding DNA) in all src transformed cell lines (Yu et
al., 1995). This ®nding set the stage for determining
whether Stat3 activation was a necessary part of
transformation in culture or merely an accompaniment. Both in our laboratory (Bromberg et al., 1998b)
and R Jove's group (Turkson et al., 1998) using
dominant negative Stat3 molecules, it was found that
in vitro transformation by src required Stat3 activation.
To test the potency of Stat3 as a sole transforming agent, we engineered a constitutively active Stat3
molecule (Stat3-C; constitutive dimerization was
achieved through cysteines inserted in the 7SH2
region) (Bromberg et al., 1999). This molecule
spontaneously dimerizes and accumulates in the
nucleus where it can bind DNA and drive
transcription. As a result, mouse and rat cells in
culture can be transformed and the resulting
transformed cells are capable of forming tumors in
nude mice. Thus by uniting the mounting clinical
evidence with the cell culture evidence it appears
highly likely that Stat3 regularly participates in
human tumors. In general, Stat3 activation has been
associated with proliferation, anti-apoptosis and
cellular transformation. However, there are a number
of examples where activated Stat3 appears to play a
role in di€erentiation and promoting apoptosis
(Chapman et al., 1999; Minami et al., 1996;
Nakajima et al., 1996; O'Farrell et al., 1998). These
observations are not necessarily surprising given the
evidence that proteins (for example myc) which
control cell proliferation are tightly linked to those
that drive cell death (Evan and Littlewood, 1998;
Hueber and Evan, 1998).
An interesting possible connection between Stat3 and
tumorigenesis is its association with c-Jun (Zhang et
al., 1999), the ®rst discovered nuclear protooncogene
(Maki et al., 1987). The c-Jun interaction does not
occur with Stat1. Furthermore, there are a number of
enhancer elements that contain c-Jun and Stat3 sites
but no reported cases of genes driven by Stat1 and cJun.
Stat5 also appears on the basis of cell culture,
animal and clinical results to be involved in tumorigenesis, apoptosis and cell proliferation. For example,
a number of oncogenes such as the BCR/ABL
tyrosine kinase and HTLV-1 leads to persistent
tyrosine phosphorylation of Stat5 (Migone et al.,
1995; Shuai et al., 1996); and a Stat5 dominant
negative protein in murine bone marrow cultures can
abrogate cellular transformation by BCR/ABL (Nieborowska-Skorska et al., 1999). A constitutively
activated form of Stat5 can obviate IL-3 dependent
growth in the pro-B cell line (BaF3) yet when the
mutant protein is hyper-activated by a ligand it
induces apoptosis (Onishi et al., 1998) through
abnormally sustained transcriptional activation of the
Jak inhibitors JAB/SOCS-1/SSI-1 (Nosaka et al.,
1999). Furthermore, activated Stat5 can promote cell
cycle progression in T cells (Moriggl et al., 1999) and
protects certain cell types from apoptosis possibly
through upregulation of Bcl-xL (Socolovsky et al.,
1999).
2471
Conclusion
Studies of STAT molecules continue to reveal information both about how these proteins participate in
triggering transcription and about the biologic e€ects
of their activation. At this time it seems safe to
conclude that Stat1 plays a role in growth restraint
while both Stat3 and Stat5 are important to unrestrained growth of many human tumors. Both molecules
may play a role in propelling at least speci®c cells
through the cell cycle but it seems most clear that they
also play anti-apoptotic roles.
One speculation that has been raised is stimulated by
the frequent co-activation of Stat1 and 3 by the same
ligand and the frequently observed Stat1 : 3 heterodimer. Perhaps these ®ndings point to a usual
balancing e€ect of Stat1 and Stat3 on each other.
Examination of downstream genes controlled by each
and the e€ect of both active simultaneously will be
important in evaluating such a possibility.
Given the evidence that a persistently activated Stat3
molecule is both necessary and sucient for cellular
transformation and that STATs are frequently constitutively activated in a variety of cancers, it is now
imperative to determine how persistent activation is
achieved (and maintained) and to search for how
persistent activation plays a role in the transformed
phenotype.
Oncogene
STAT proteins and growth control
J Bromberg and JE Darnell Jr
2472
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