From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
C-MYB
but
not
C-MYC
Suppresses
the
of Hemoglobin
by Murine
By Edward
Clonal
lines
have
of Friend
been
c-myb
expression
levels
of abnormally
and
fail
to
dimethyl
the
two
differentiate
asked
plasms.
For
leukemia,
breast
somal
translocations,
novel
in the
or deregulated
family
certain
gene
c-onc
have
been
naturally
animal
of
after
induced
genes
c-onc
a lengthy
usually
reported
of monoclonal
probably
in the
they
Expres-
results,
of tumors,
origin.9”0
Thus
most
implicate
changes
as necessary,
although
emergence
c-myc
of the neoplastic
the
role
of normal
genes
c-onc
proliferation
processes
is less certain.
Transient
in the expression
of genes such as c-myc,
c-myb,
and
c-los
have
cent
cells
into
most
ships
the
shown
cell
From
not
and
the
Room
A514,
the reentry
terminal
in their
between
been
the Section
atrics
whereas
by alterations
distinctions
have
to precede
cycle,
accompanied
cases
Arbor,
been
rigorously
MSRB
I, Box
on
Cellular
0624.
The
differentiation
In
relation-
of Pedi-
Molecular
Biology,
Ann
MI.
Submitted
September
Supported
(HL33741)
Edward
American
Address
by
and
V.
19. 1988;
grants
the
from
reprint
the
American
Prochownik
Heart
accepted
is
National
Heart
an
October
Established
of
of
to Edward
c-myc
accelerates
These
findings
simultaneous
regulation
for the diffenenis known
proto-oncogene
concern-
products
of the functions
in F-MEL
cells
these
might
leading
to
transfected
functions
with
not
have
been
toward
the relative
understanding
contni-
cells
Health
functions
inducing
genes
to
to
hemin.
hemoglobin
We
to hemin
This
without
have
c-myc
initiate
found
con-
that
sequences
are
whereas
induction,
Ffully
those
sequences
are not. It appears that aberrant
exerts
a more profound
suppressive
effect
differentiation
that
c-onc
exposure
transfected
responding
not
these
differentiation.27
expressing
c-myb
c-myb
expression
on F-MEL
that need
of
expressing
of
of
following
be
so as to
dependent
can
on
c-myc
include
actual
expression,
responses
diffenentia-
while
inhibitory
is permissive
nevertheless
be dissociated
those
terminal
from
this
to
for those
state.
Michigan.
Investigator
V. Prochownik,
RNA
Little
some
to commit-
endogenous
antisense
normally.
in a
although
leading
of
con-
results
differentiation.22
either
terminal
of
the
MATERIALS
Association.
requests
The
plasmids
sequences
processes
of
these
murine
differentiate,
are required
tion. On the other hand,
terminal
differentiation,
19, 1988.
Institutes
Association
c-myb
transcripts
is capable
current
MEL
Department
ofMichigan,
Friend
differentiation.
and
synthesis
compound
expression.”’6
University
termi-
terms.
expressing
capable
and
or
plasmids,’7
step
hemoglobin
established.
ofHematology/Oncology,
Committee
rantly
of quies-
and casual
causal
the
bution
of c-myc
and c-myb
to the suppression
of F-MEL
differentiation,
we have examined
the ability
of clones aben-
in differentia-
tion and
increases
those
the contribution
expression
coordinate
While
in molecular
As an initial
In contrast,
of
have occurred
expression
defined
terminal
use
at which
however.
the
suppression
to proceed
levels
be acting,
to
of the
the
c-myb
process
the
than
of
from
used
cells
F-MEL
and
expression
terminally
the
that
commitment
phenotype.
is often
suggested
ing
to
some
through
potentiates
globally
functions
the
have
c-myc
cells
execute
have
to hemin
a more
cell line to study
F-MEL
these
and
tiation
others
Conversely,
of c-myc
usually
production
expression
for the full
insufficient
been
carcinogens.’8
of tumorigenesis
and/or
structure
in c-onc
full-length
transcripts
exerts
be dissociated
(F-MEL)
expression
of
of
and
into
may
prevent
hemoglobin,
& Stratton. Inc.
we
ment.’72’
of
refractory
F-MEL-differentiated
otherwise
erythroleukemia
of c-onc
gene
failure
well
were
c-myb
that
c-myc-transfected
induction
state.
taming
in experimental
animals
may
by Grune
transfection
fractions
and
on oligoclonal
concepts
have
and
Chromoresult in
level
substantial
by chemical
period,
be
and chronic
myin members
of the ras
carcinomas
in transgenic
latency
contemporary
in
to
on
can
Recently
neo-
reported
that
of
the
cells
appears
differentiated
1989
oncogenes
exposure
for
effect
c-myc
nally
that
allows
It thus
events
S
found
c-myb-transfected
does
nonlymphoblastic
transcripts,
lymphoma
mutations
occurring
tumors
sion
been
as acute
whereas
at
inhibi-
Cells
hemin
suppressive
differen-
cellular
to
of
express
of malignant
cancer,
and neuroblastoma.”3
which
at the molecular
characterized
in Burkitt’s
elogenous
leukemia.4’5
Point
gene
their
could
of terminal
implicated
diseases
levels
exert
It was
cells
induction.
presence
clones
pathogenesis
genes
have
c-onc
transcripts
relative
absence
have
in the
in such diverse
amplified
these
high
Expression
Prochownik
tiation.
or
produce
the
the
might
whether
studies
genes)
example,
(c-onc
in
determine
functions
UMEROUS
clones
cells
Nonterminal
Erythroleukemia
V.
c-myc
with
proto-oncogene
proto-oncogenes
we
differentiated
N
These
regulated
To
(F-MEL)
transfection
plasmids.
terminally
effects.
erythroleukemia
following
sulfoxide.
which
tory
murine
generated
Hemin-Induced
MD,
PhD,
AND
METHODS
cells
in Dulbecco’s
modified
Eagle’s minimal
(DMEM)
supplemented
with 10% fetal calfsenum
L glutamine
and antibiotics.
Individual
F-MEL
Cell
culture
and
induction.
F-MEL
(clone
745) were
essential
medium
(FCS), 2 mmol/
Section ofHematology/Oncology,
Department
ofPediatrics
and the
Committee
on Cellular
and
Molecular
Biology.
Room
A514,
MSRB
I, Box 0624, The University
of Michigan,
Ann Arbor, MI
grown
48109.
on human c-myb
sequences
were obtained
as previously
descnibed.2#{176}22In addition
to
the above culture
conditions,
these clones were maintained
in
medium containing
0.25 mol/L
methotnexate.
A clone of F-MEL
cells, designated
onc- was obtained
following
transfection
with a
plasmid
lacking c-onc sequences
and was also maintained
in methotrexate-containing
medium.
Cells were routinely
grown in I 50-mm
amplified
The publication
charge payment.
“advertisement”
indicate
©
1989
costs
ofthis
article
This
article
must
in accordance
by Grune
& Stratton.
0006-4971/89/7303-0010$3.00/0
782
with
this fact.
Inc.
were
defrayed
therefore
18 U.S.C.
in part
be hereby
section
by page
marked
1 734 solely
to
copies
of
Blood,
tnansfected
munine
Vol 73, No 3 (February
clones
expressing
c-myc
1 5), 1989:
pp
782-786
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
MURINE
ERVTHROLEUKEMIA
783
CELLS
Petni dishes with the addition of fresh medium every two to three
days. For the induction
of terminal
differentiation,
dimethyl
sulfoxide (DMSO)
was added to a final concentration
of 1.8%. To induce
hemoglobin
synthesis without
terminal
differentiation,
bovine hemin
(Sigma,
St Louis) was added to a final concentration
of 100 mol/L.
Cells were stained with benzidine
after five days to determine
the
fraction
of hemoglobin-beaning
cells.
Nucleic
acid analyses.
The detection
of transfected
c-myc
or
c-myb
sequences
used previously
described
51 nuclease
protection
assays.20’2’
In the former
case, a 940-bp
long NdeI-XhoI
DNA
fragment
from the plasmid
pSV2myc-dhfn
was end labeled at the
XhoI
site and used to detect
endogenous
and exogenous
c-myc
transcripts
simultaneously.#{176} In the latter
case, a 1.5-kb
end-labeled
were
purified
was
redissolved
filter
of total
cellular
RNA
and
i05-
nuclease
(Sigma),
precipitated,
lyophilized,
and
resolved
on either
1% (for c-myb) or 2% (for c-myc) aganose gels. After drying, the gels
were exposed to x-ray film at - 80#{176}C
in the presence of an intensifying screen.
To detect individual
globin-chain
transcripts,
total cellular
RNAs
A
6
12345
MD).
The
filter
10 ig of each RNA
onto a nitrocellulose
a dot-blot
manifold
was baked
and
then
hybrid-
under
standard
conditionsa2
with nick-translated
probes
derived from either the munine a’-globin
gene (3.1-kb
SstI fragment23) or the munine 9-globin
gene (3.8-kb
PstI-Bg1II
fragment24).
The munine
gene was a generous
gift of Dr
Richard Rifkind (Memorial
Sloan Kettering Cancer Institute).
RESULTS
Characteristics
ofc-mycclones.
We studied
four
and
c-myb--transfected
individual
F-MEL
F-MEL
clones
that
had
stably transfected
with a recombinant
plasmid
containing an SV4O-murine
c-myc
cDNA
transcription
unit and six
clones
10 g
F-MEL
clones.
and then spotted
same buffer using
ized
ization
contained
in the
Gaithersburg,
been
reactions
individual
in 20 x SSC
equilibrated
(BRL,
HindIII
fragment
from the plasmid
pMbMl-dhfn
was used to detect
the expression
of transfected
human c-myb
sequences.2’
All hybrid2 x l0 dpm of probe in a total volume of 10 L of hybridization
buffer (80% formamide,
400 mmol/L
NaC1, 40 mmol/L
PIPES, pH
6.4, 1 mmol/L
EDTA).
Hybridizations
were allowed to proceed for
16 hours, at which time they were digested
with 90 units of Si
from
that
had
transcription
c-myb
tandemly
been transfected
unit. In both
linked
with
a
murine
cDNA
also driven
by an SV4O
for the
controlled
amplification
the
respective
vations).
myc
All
hybrid
endogenous
B
of the
c-myc
transcripts
c-myc
dihydrofolate
viral
(Fig
clones
reductase
promoter.25
and
sequences
c-onc
with
an SV4O-humancases c-onc
sequences
were
high-level
This
1 and unpublished
contained
at
levels
at
message
(Fig
1A).
exogenous
least
Four
allowed
expression
equal
to
of
obserSV4Othose
of
of the six c-myb
1234567
11OO-
940’-
98O’92O’440
72O4O0
N
-
*
-‘Ic
-
.
H
x
X
040M
eeoc
3S5/eoore
I
-c,
-*
*
-*
-sic
ieooc
eeoc
floe
Fig 1
Expression
of transfected
c-onc plasmids in individual
F-MEL clones.
(A) Detection
of myc transcripts.
Total RNAs from each of
the indicated
cloned cell lines were hybridized
with the 940-nt
long end-labeled
Ndel-Xhol
Si probe shown in the bottom
portion
of the
figure.
Endogenous
c-myc transcripts
protect
385 and 400-nt
long probe fragments
whereas
those originating
from the pSV2myc-dhfr
vector protect
a 440-nt
long fragment.
RNAs were from onc-F-MEL
cells (lane 1 ). onc-F-MEL
cells treated
with DMSO for 8 hours (lane 2).
myc-lO
cells (lane 3). myc-12
cells (lane 4). myc-14
cells (lane 5). myc-15
cells (lane 6). (B) Detection
of myb transcripts.
RNAs were
hybridized
with the 1 .5-kb end-labeled
HindIlI human c-myb-specific
fragment
shown at the bottom
of the figure. The protected
fragments
shown are the result of protection
of the probe with unspliced
RNA (1 .1 00 nt). spliced RNA using either of two splice-acceptor
sites within
the pMbMl
plasmid
(980 and 920 nt). spliced RNA using a splice-acceptor
site in the 5’-untranslated
region of c-myb sequences
(720 nt).
RNAs were from onc-F-MEL
cells (lane 1), myb-76A
cells (lane 2). myb 848 cells (lane 3). myb 89A cells (lane 4). myb-97A
cells (lane 5).
myb-85C
cells (lane 6). myb-85A
cells (lane 7).
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
784
EDWARD
clones
contained
exogenous
to endogenous
parable
(85C
clones
(Fig
and
1B).
clones
As
85A)
of F-MEL
F-MEL)
were
results
for
cells
amplifiable
that
used.
These
com-
whereas
two
transfected
with
c-onc
sequences
(onc-
had
with
individual
stably
lacking
are
levels
lower
experiments,
had been
clones
here
at levels
levels,
significantly
these
plasmids
reported
transcripts
message
contained
a control
similar
the
hybrid
c-myc
similar
one
properties,
such
and
representative
strikingly
types:
the
four
induction
percentage
either
the
DMSO
of benzidine-positive
uninduced
(1.8%)
state
was
F-MEL
cells,
fected
clones
showed
of inducing
DMSO,
greater
than
refractory
85C
c-myb
transcripts
and
consistent
c-myb
inhibit
dependent
and
onc-F-MEL
In marked
contrast,
refractory
to
whereas
cells
respectively).
F-MEL
that
occurs
that
the
the
with
studies
showing
as
terminal
has
been
to be capable
shown
in F-MEL
synthesis
cells
differentiation.26’27
was
next
examined
Each of the c-onc
for benzidine
five-day
to 100 imol/L
exposure
Table
.
1
of
without
and
a dose-
inducing
hemo-
causing
terminal
clones described
above
positivity
following
a
hemin.
The
results
for
none
of
Staining
or Individual
or c-myb-Transfected
F-Mel
Control,
were
Uninduced
that
the
benzidine-positive
also
were
partially
responded
responsive
to hemin.
ability
gene
they
clones
in
These
c-myc
In addition,
products
act
at
phenotype
they
different
and that,
hemin
inhibitory
tmol/L
at least
cell
growth
for
over
suggest
to
in the
manner.
to
normal
hemin
to
not
points
so in a dose-dependent
do
was
demonstrated
100
deregulated
to hemin.
exposure
cases
of
In
growth.
All
even
when
rates
1 week
(unpublished
Hemin-mediated
induction
of
genes.
Since
the benzidine
reagent
was not possible
to state
unequivocally
a-
and
measures
that
more
duced
3-globin
a- and
from
individual
been
treated
detail,
we
and
c-myc-
that
RNAs
were
whether
Total
were
with
were
c-myc-
Cells
Hemin
1
97
30
onc-F-MELt
0
89
38
Myc-lO
0
1
45
Myc-12
0
0
66
Myc-14
0
0
44
Myc-15
0
0
37
Myb-76A
0
0
6
Myb-84B
Myb-89A
0
0
3
five
1
0
5
observed.
Myb-97A
2
0
6
Myb-85C
0
51
40
expressed
abundant
results obtained
with
Myb-85A
1
42
28
purified
or 100
and the filters
had
.tmol/L
were
first
probe.
As
expression
of
exposure
to DMSO,
cells expressed
eight-
a’-globin
mRNA.
Following
a five-day
untransfected
F-MEL
and onc-F-MEL
DMSO
pro-
or that
DMSO
dot blotted,
and
clones
uninduced
1.8%
all
this
DMSO
RNAs
either
it
expressing
To study
c-myb--transfected
transcripts.
clones
for five days
The
asked
heme,
hemin-induced
c-myc-transfected
clones were coordinately
the factors necessary
for hemoglobin
assembly.
question
in
hemin-induced
f3-globin
only
hybridized
with
a 32P-labeled
munine
a’-globin
seen in Fig 2A, uninduced
clones showed little
Clones
% Benzidine-Positive
Clone
85A)
c-onc
the
F-MEL
hemin.
Benzidine
and
to
97A)
(s6%
that
DMSO
were also
refractory
and
findings).
c-myc
in
clones
c-myb,
case
and
are
differentiation
induction
two
the differentiated
cultured
results
that
totally
89A,
hemin
upon
two
suppress
clones
The
were
84B,
the
indicate
trans-
(51%
DMSO.
suppress
DMSO-induced
terminal
differentiation
does
necessarily
extend to the state of nonterminal
differentiation
cells
inducible
with
to
Of note was that c-myb
low levels of exogenous
partially
that
76A,
(85C
in
and
observed
results
manner.
Hemin
globin
treatment
contain
our previous
with
Following
was
in
untransof the
staining
1), were
benzidine-positive
any
benzidine
induction.
which
(Fig
exposure
and c-myb-transfected
c-myc
85A,
nor
of control
staining.
to DMSO
clones
42%
(2%).
80%
reported,20’2’
previously
were
agent
clone
1). Neither
cells,
significant
in each
a five-day
(Table
onc-F-MEL
intense
demonstrated
or following
quantitated
fected
absence
cells
clones
(clones
to DMSO
The
what
PROCHOWNIK
Both onc-F-MEL
cells and each of the c-myc-tnansfected
clones
displayed
significant
benzidine
staining
with
this
reagent.
C-myb-transfected
clones, in contrast,
were of two
cells),
clone.
from
different
V.
to 12-fold
more a’-globin
transcripts
(Fig 2B) than did
untreated
cells. All of the myc clones and four of the six myb
clones failed to express globin.
The exceptions
to this were
fold
Untransfected
F-MEL
The indicated
medium
clones
supplemented
were
split and fed every
end
of five
benzidine.
The results
experiments
days,
grown
in either
with
1 .8%
other
day to maintain
aliquots
A minimum
shown
were
of 200
of
cells
not present.
in response
The clones
to DMSO
included here.
medium
mol/L
hemin.
logarithmic
removed
counted
a representative
growth.
and
When
Two
exhibited
or hemin.
Typical
results
degrees
with
a different
(Fig
treated
pattern
Untransfected
of
and
globin
DMSO,
1B,
with
Table
100
1).
tmol/L
a’-globin
hemin
for
expression
onc-F-MEL
cells
was
once
again
transcripts.
Contrary
to the
hemin was capable of inducing
However,
four
with
to five
clone
were
clones
Cells
hemin
induction.
clones
myb-85C
are
of
Northern
blots
None
human
c-myb
hemin.
and
Hemin,
six
and
the
2D-F).
ible
the
Once
Essentially
or
of differentiation
one such
to DMSO
the
chain synthesis
in all four myc clones, consistent
results
of benzidine
staining
shown
in Table
1.
following
transfection
of a
except that c-myc sequences
identical
responsive
a’-globin
with
the
for each determination.
experiment.
days,
and myb-85A,
which
expressed
transcripts
and that were at least
or in
At the
stained
clones myb-85C
of human
c-myb
partially
with each clone.
tSeveral
F-MEL
clones
were obtained
plasmid that was identical to pSV2myc-dhfr
were
or iOO
were
cells were
here are from
were performed
DMSO
regular
seen with
low levels
however,
clones
the
(Fig
with
clones
were
myb-85C
results
was capable
refractory
to
seen were
with
2C).
were
hybridized
transcripts
remained
the exceptions
results
of the myb
Only
clones
myb-85A
same
were
paralled
myb
again,
seen
when
a fl’5-globin
producing
inducible
and
large
with
myb-85A
seen with
of inducing
the
identical
probe
(Fig
amounts
either
were
of
DMSO
induc-
cr’-globin
probe.
fl-globin
tran-
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
MURINE
ERVTHROLEUKEMIA
785
CELLS
I
Fig 2.
Detection
of globin
transcripts
in individual
F-MEL
clones by dot-blot
analysis.
Ten
micrograms
of each RNA were
spotted
onto
nitrocellulose,
baked.
and
hybridized
with
either
a’-globin
(A through
C)
or
fl”-globin
(D
through
23456789101112
A
B
F)
probes.
Each clone was either
untreated
(A and D) or treated
for five days with either
1.8%
DMSO
(B and E) or 100 gsmol/L
hemin
(C and F). RNAs
were
from untransfected
F-MEL cells
(lane 1). onc-F-MEL
cells (lane
2). myc-lO
cells (lane 3). myc12 cells (lane 4). myc-14
cells
(lane 5). myc-1 5 cells (lane 6).
myb-76A
cells (lane 7). myb848
cells
(lane
8). myb-89A
cells (lane
9). myb-97A
cells
(lane 10). myb-85C
cells (lane
1 1). myb-85A
cells (lane 12).
C
D
E
F
scripts in all of the myc clones
but only in the two
expressing
the lowest levels of c-myb
transcript.
myb
demonstrated
clones
can
DISCUSSION
C-myc
ral
and
c-myb
transforming
tively.
oncogenes,
The
the
v-myc
avian
v-myc
comprises
myelocytomatosis
oncogene
v-myb
counterparts
termed
oncogene
in the
of the
(MC29),
avian
genome
the
myeloblastosis
the
c-myb
Cole’7
V-myb,
on the
only
cytic
cells
in culture
commitment.
This
stage in the F-MEL
leukemias
narrower
in
vivo28.3’
way
of the
related
not
immature
yet
finding
whether
and
the
tumors
that
to relatively
myeloblastic
certain
of v-myb
hematopoietic
to the
primarily
restricted
is
spectrum
phenotype
in any
induces
It
neoplastic
primitive
expression
undifferentiated
We
have
previously
transfected
with
unable
demonstrated
either
c-myc
to undergo
that
on c-myb
F-MEL
DMSO-induced
terminal
at
is
onstrated
ruses.
plasmids
differentia-
They
normal
are
mandatory
F-MEL
While
inhibit
quantitate
for
the
it is clear
that
regulation
terminal
of c-myc
erythnoid
and
is
c-myb
differentiation
of
cells.
erythroid
this
proliferative
points.
deregulation
differentiation,
effect
capacity)
as to whether
different
coordinate
and
the
(ie,
have
two
In
loss
the
c-myc
not allowed
experiments
are
or c-myb
parameters
of hemoglobin
oncogenes
the
of
can
used
to
and
expression
for a determination
acting
reported
here,
or
it
also
of
of these
results
so as to include
the
the
those
of
of Coppola
cells,
are able
leading
acts
func-
state.
F-MEL
steps
myc
to
erythroid
at a relatively
late
program.
in agreement
the v-myb
findings
is
globally
a more
differentiating,
that
Using
proposed
with
transformed
the
recent
findings
myeloblasts
chick
bone
oncogene
is
that
cells
to retain
suggested
We
but
have
also
recently
levels
of
was
their
derived
marrows,
they
dominant
inhibited
over
dem-
v-myc
in opposite
to
to allow
to enter
of c-myc
tion
phenotype.
would
pathway
prevent
but
might
only
differen-
On
provided
the
other
a prolifer-
to explain
product
ways.22
can
how
affect
According
high
or
F-MEL
to this
model,
levels that normally
accompanies
differentiation
of F-MEL
cells
cells
ultimately
cessation
not
on myelo-
otherwise
capacity.
a model
gene
committed
what
proliferative
no effect
allow
differentiation.
proposed
in c-myc
terminal
and
v-myb
c-myc
the
exerted
did
proliferative
that
the reduction
DMSO-induced
necessary
v-myc
but
differentiation
differentiated
at common
c-myb-transfected
exert
with
differentiation
tiated
low
that
some
differentiation
genes.
experiments
not
of terminally
monocytic
drive
similar
inducing
by its ability
to reverse the relatively
mature
macrophagelike
phenotype
of cells transformed
by v-myc-containing
retrovi-
ative
and
of
differentiation,26’27
c-myc-transfected
AMV-infected
that
they
of these
that
suggests
al.33
from
hand,
implication
cells
are
et
tion.#{176}’2’This occurs as a result of the constitutive
expression
of these plasmid-derived
oncogene
transcripts
in the face of
relatively
normal
regulation
of
the
endogenous
cellular
The
F-MEL
least
results
Ness
directly
stably
cells
expression
Our
is
hemato-
on
not capable
execute
of
it induces
c-myb
to
the
relatively
cells.32
poietic
are
and
but
can
showed
vivo.
myelomono-
capable
interpretation
is consistent
who
although
transforms
c-myc-
product
interpretation
and
sarcomas,
carcileukemias
in
hand,
in
is
gene
effect
and
other
of terminal
differentiation
processes
that are normally
capable
tioning
independently
of the terminally
differentiated
This
virus
which
simplest
(AMy).
V-myc
transforms
both fibnoblasts
cytic cells in vitro and induces
soft-tissue
nomas,
and relatively
mature
myelomonocytic
myelomono-
hemin,
absence
role
The
suppressive
of
whereas
this
cells.
that
of retroviv-myb
respec-
and
part
virus
is found
perform
F-MEL
the cellular
are
that
in the
hemoglobin
becomes
and
the
to exit
a one-way
not
into
be
of
constitutive
the
is
cycle
leading
the
fully
expression
terminal
expected
mitotic
path
expression
High-level,
entry
the
differentiato
prohibit
the
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
EDWARD
786
expression
of cellular
functions
that
this pathway
(ie, hemin-induced
Although
less is known
regarding
might
operate
seem
that
least
some
to inhibit
the
F-MEL
in the case of F-MEL
nonterminal
can
be expressed
hemoglobin
level
at which
cells
c-myb
it can also influence
pathways.
This
effect,
myb-induced
it would
differentiation,
differentiation
be a direct
outside
expression).
at
could
and
more
the
genes
such
likely,
this
inhibition
effect
of any
with
or a
Alternatively,
in which
a cellular
expression
of its association
by myb
transcription.
orchestrate
to the
regardless
actual
is an indirect
it controls
is inimical
as the
on globin
protein
V. PROCHOWNIK
myb
environment
differentiated
the terminal
and
that
function,
state.
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From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
1989 73: 782-786
c-myb but not c-myc suppresses the hemin-induced nonterminal
expression of hemoglobin by murine erythroleukemia cells
EV Prochownik
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