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J Biol Chem, Vol. 274, Issue 26, 18141-18144, June 25, 1999
From the Department of Biochemistry and Molecular Biophysics and
Microbiology, Columbia University College of Physicians and Surgeons,
New York, New York 10032
v-Abl, encoded by the Abelson murine
leukemia virus, is a non-receptor tyrosine kinase with potent oncogenic
activity in mice (for review, see Refs. 1 and 2). A similar human
oncoprotein, BCR-ABL, is critical in the pathogenesis of 95% of
chronic myelogenous leukemia
(CML)1 and 10% of acute
lymphocytic leukemia (for review, see Refs. 3 and 4). The c-Abl
proto-oncoprotein was identified as the normal cellular homolog of
v-Abl (for review, see Ref. 2). The increased tyrosine kinase
activities of v-Abl and BCR-ABL, compared with the cellular c-Abl,
correlate with their transforming activities. The molecular mechanisms
by which these activated tyrosine kinases cause malignant
transformation have remained obscure until the last few years when
there have been reports that multiple signaling pathways are activated
by v-Abl and/or BCR-ABL. The intent of this review is to: 1) synthesize
the current understanding of v-Abl signaling, 2) identify those
signaling pathways that are critical for transformation, and 3) compare v-Abl signaling to BCR-ABL signaling, which has been reviewed elsewhere
recently (for review, see Refs. 5 and 6).
There are several reasons for studying v-Abl. First, it is a potent
transforming oncoprotein, and understanding its immediate substrates
and final targets will help us understand the processes required for
malignant transformation. Second, although in vitro v-Abl
can transform many cell types, in vivo it only transforms pro or preB cells, the early B-lineage cells that have partially or
completely rearranged their heavy chain genes (for review, see Ref.
12). The striking pro/preB cell tropism for transformation, in the
absence of any evidence of pro/preB-specific viral infection, is likely
to reveal regulatory paths that are unique to the early B-lymphocyte
lineage. Finally, studying v-Abl in mice provides a convenient approach
to identify activities that may be common to (or shared by) v-Abl and
the human oncoprotein BCR-ABL.
The v-abl oncogene in Abelson murine leukemia virus encodes
a fusion protein in which a portion of retroviral Gag protein replaces
the SH3 domain of c-Abl (Fig. 1) (for
review, see Ref. 1) (7, 8). Removal of the SH3 domain constitutively
activates the tyrosine kinase, and a myristoylation site in the Gag
moiety confers localization to the inner plasma membrane; both
modifications are important in the transforming activity of v-Abl (9).
Infection of neonatal mice by Abelson murine leukemia virus results in
rapid, 100% fatality because of pro/preB cell tumors. In
vitro, v-Abl transforms pro/preB cells as well as myeloid cells
and a subset of 3T3 fibroblasts (10) (for review, see Refs. 11 and 12). The human oncogene, BCR-ABL, is the result of a reciprocal
chromosomal translocation in which the breakpoint cluster region
(BCR) gene on chromosome 22 becomes fused to the
c-ABL proto-oncogene on chromosome 9. It encodes a fusion
protein in which part of the SH3 domain of c-ABL is replaced by
portions of the BCR protein (for review, see Refs. 3 and 4). Different
forms of BCR-ABL result when different portions of BCR are included;
however, all BCR-ABL proteins have tyrosine kinase activities
intermediate between the weaker c-ABL and the stronger v-Abl (13).
In vitro BCR-ABL expression confers growth factor
independence but is fully transforming only for certain cells (for
review, see Ref. 14). v-Abl and BCR-ABL share a C terminus that is
unique among non-receptor kinases. It contains a nuclear localization
signal, a proline-rich region capable of associating with
SH3-containing proteins, a sequence-independent DNA-binding domain and
an actin-binding domain (for review, see Refs. 15 and 16).
Data from a variety of experiments show that signaling through the
GTP-binding protein p21ras is essential for transformation by
both v-Abl and BCR-ABL. Inhibition of p21ras
activity by antisense oligonucleotides to p21ras
(17), microinjection of a blocking monoclonal antibody to
p21ras (18) or expression of the catalytic domain of Ras GAP
(19) all block transformation by v-Abl and BCR-ABL. Dominant negative forms of p21ras inhibit
v-Abl-dependent induction of c-myc transcription
(20), fibroblast and bone marrow cell transformation by v-Abl and
BCR-ABL (19), and the anti-apoptotic effect of BCR-ABL (21). Although other Ras family proteins have been described, their role in v-Abl or
BCR-ABL signaling has not been explored (for review, see Ref. 22).
How Does v-Abl Activate p21ras?--
There
are multiple links from v-Abl to p21ras.
Although critical tests have not been done, it seems likely that more
than one connection to p21ras may be required to
mediate full oncogenic activity of v-Abl. One clear link to
p21ras is direct binding of Shc to the SH2
domain of v-Abl, which may allow tyrosine phosphorylation of Shc by
v-Abl and subsequent activation of the Ras pathway through assembly of
a signaling complex with Grb2-mSos (23). Another connection is binding
of p62(dok) to v-Abl. Binding to v-Abl causes phosphorylation of p62(dok), which then binds RasGAP, a negative regulator of
p21ras (24, 25). It is not known how
phosphorylation may alter p62(dok) activity or whether a ternary
complex may form in which v-Abl phosphorylates RasGAP directly,
possibly inactivating RasGAP (24). p62(dok) is also phosphorylated in
cells expressing BCR-ABL (25), another Dok-like protein, which
interacts with v-Abl, has recently been identified and may play a
similar role.2
There is also evidence for a link between the C terminus of v-Abl and
p21ras because p21ras
complements C-terminal mutants of v-Abl for bone marrow cell transformation (26). The C termini of v-Abl and BCR-ABL are the same
(Fig. 1); thus it is likely that both proteins make similar connections
to p21ras. A variety of proteins bind this
region, particularly SH3-containing proteins that associate with the
proline-rich region in the C terminus. Adaptor proteins Crk, Crkl, Nck,
and Grb2 can bind this region (27). Of these, the Crkl adaptor protein
may be a functionally important interactor because it is
hyperphosphorylated in CML cells containing BCR-ABL (28). However, the
role of Crkl in BCR-ABL signaling is controversial because deletion of
the Crkl-binding site in the C terminus of BCR-ABL impairs fibroblast
transformation (29) but not myeloid cell growth factor independence
(30) (for review, see Ref. 31).
Abl interactor proteins Abi-1 (32) and Abi-2 (33) bind to the
C-terminal proline-rich region of v-Abl and BCR-ABL. Ectopic expression
of Abi-1 inhibits v-Abl transformation (32). Consistent with this
finding, BCR-ABL induces proteasome-dependent degradation of Abi-2, which may be important to block its inhibitory activity and
allow cell transformation (34). These adaptor proteins appear to
inhibit p21ras activation and thus block v-Abl-
and BCR-ABL-dependent transformation. Abi-1 associates with
Eps-8 (35), a substrate of the epidermal growth factor and
platelet-derived growth factor receptors, that also associates with Shc
(36) and inhibits ERK activation in response to epidermal growth
factor signaling.2
BCR-ABL also binds directly to Grb2 (37). Because this association
involves the BCR portion of the protein, which is absent in v-Abl, this
connection is unique to the human oncogene. However, BCR-ABL also
connects to p21ras and Grb2 via Shc (38),
probably by virtue of Shc binding to the SH2 domain (23).
What p21ras Effectors Are Important following
v-Abl Activation?--
Although p21ras often
activates the Raf serine kinase leading to activation of ERK, for
v-Abl, there are branch points from Raf that exclude ERK. ERK is
activated in v-Abl-transformed cells by a poorly understood
Raf-independent path (39) and is not activated by BCR-ABL (40, 41).
A Ras/Raf-dependent pathway is required for
v-Abl-dependent induction of c-myc
transcription, which appears to be ERK-independent (20). Expression of
dominant negative Myc blocks transformation by either v-Abl or BCR-ABL
(42), establishing the importance of this pathway. In the
c-myc induction pathway Raf ultimately activates
cyclin-dependent kinases, which phosphorylate Rb family proteins and thus activate E2F transcription factors (20). In addition
to c-myc, v-Abl also induces mRNA encoding other
E2F-dependent genes, which are required for cells to enter
S phase including dihydrofolate reductase, ribonucleotide reductase,
cyclin A, and cyclin E.3 The
connection from v-Abl/p21ras/Raf to
cyclin-dependent kinases may be through activation of the Cdc25A
phosphatase (43), but there is presently no direct evidence for this.
BCR-ABL also activates E2F proteins, leading to induction of
c-myc transcription (44), presumably by a
Ras-dependent pathway similar to that for v-Abl (20).
Recently, expression of the p19ARF gene has been
shown to be increased in a way that depends on
p21ras (45), E2F activators (46), and c-Myc
(47). Up-regulation of p19ARF leads to an increase in p53
levels (for review, see Ref. 48). Because v-Abl activates
p21ras and E2F proteins and induces c-Myc, it
may be that v-Abl also causes an increase of p53 via
p19ARF. It is attractive to speculate that relative
induction of p19ARF versus c-myc and
S phase genes might determine whether a cell becomes transformed or
undergoes apoptosis in response to v-Abl. In support of this
notion, there is evidence that a p53-dependent path
inhibits transformation by v-Abl in
vivo4 and in
vitro (49) and plays a role in BCR-ABL-dependent blast transformation in CML (50). Also, v-Abl can up-regulate
p19ARF and cause p53-dependent
apoptosis in Abelson virus-infected primary preB cells (51). Unlike
preB transformants derived from normal mice, those from
Ink4a/Arf Dominant negative Rac blocks v-Abl transformation, establishing a
requirement for Rac activation in v-Abl transformation (52). In this
system, ERK and JNK activation was also inhibited by dominant negative
Rac, suggesting that these effectors are downstream of v-Abl/Rac (52).
Rac is not required for v-Abl-dependent induction of
c-myc transcription, which depends on
p21ras and Raf (20), but Rac is necessary for
activation transcription dependent on serum or
12-O-tetradecanoylphorbol-13-acetate response elements (52).
Studies with dominant negative Rac also show that Rac is required for
BCR-ABL-induced leukemogenesis (53). It is not currently clear whether
activation of Rac by v-Abl or BCR-ABL proceeds directly or by
activation of p21ras or PI3K, as has been
observed in other systems (for review, see Ref. 22).
JNK is activated by both v-Abl and BCR-ABL but by different pathways.
v-Abl-dependent JNK activation requires Rac (52), whereas
BCR-ABL-dependent JNK activation requires
p21ras (41). Phosphatases may provide another
path to JNK activation because BCR-ABL associates with SHPT1, which
regulates JNK activity (54). Dominant negative c-Jun inhibits
BCR-ABL transformation, demonstrating the importance of JNK activation
for BCR-ABL transformation (41).
v-Abl and BCR-ABL, but not c-Abl, associate with and activate PI3K
(55). Interestingly, the accumulation of PI3K products phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate correlates better with v-Abl or BCR-ABL transformation than does association of Abl kinases with PI3K (55, 56). v-Abl and
BCR-ABL may activate PI3K by more than one pathway because activated
p21ras activates PI3K in other systems (57), and
recent work suggests activation of Jak1 by v-Abl might contribute to
PI3K activation (58). Inhibition of PI3K blocks proliferation of
BCR-ABL-dependent cells, establishing the importance of
PI3K for BCR-ABL activity (59). Akt kinase is an important effector of
BCR-ABL-activated PI3K because a dominant negative mutant of Akt
inhibits BCR-ABL-dependent transformation of murine bone
marrow cells (60).
IL-3-dependent mast cells transformed with a
temperature-sensitive form of v-Abl revealed that v-Abl activates
phospholipase C-mediated breakdown of phosphatidylcholine, generating
diacylglycerol, which then activates PKC (61). The anti-apoptotic
effect of v-Abl in this system was blocked by inhibiting PKC activity,
indicating a functional role for PKC. Subsequent studies in the same
cells show that the v-Abl/PKC pathway causes an increase in
bcl-XL mRNA, which may be responsible for
the anti-apoptotic effect (62).
The recent discovery that STAT1, -3, -5, and -6 are constitutively
activated in v-Abl-transformed proB or preB cells (58, 63) led to the
attractive model that constitutive activation of STATs by v-Abl confers
cytokine independence and is critical for transformation. In normal
cells, nuclear translocation of STATs occurs only in response to
cytokine binding to receptor and activation of receptor-associated
Janus kinases (Jaks) (for review, see Ref. 64). Evidence is
accumulating to support the constitutive STAT activation model. Jak1
and Jak3 associate directly with v-Abl (58). Deletion of 200 amino
acids in the DNA-binding portion of the v-Abl C terminus (Fig. 1) that
are required for association with Jak1 results in a mutant v-Abl, which
cannot provide cytokine-independent survival of BAF/3 pro-B
lymphoblastoid cells. This provides evidence that Jak binding and STAT
activation are important for v-Abl-dependent transformation
(58). Furthermore, in murine tumors resulting from
abl/myc retroviruses, constitutive activation of
STAT3 makes the cells IL-6-independent (65). However, cytokine
independence is not sufficient to cause transformation because a
combination of IL-4 and IL-7 signaling cannot substitute for an active
v-Abl kinase in transformed pre-B cells (66). STAT-independent paths
from activated Jaks may also be important for v-Abl activity because
cytokine-dependent suppression of apoptosis (67) and
induction of the anti-apoptotic gene bcl-XL (68) result from a Jak-dependent, STAT-independent path in
myeloid cells.
Contrary to v-Abl, BCR-ABL does not activate STATs by a
Jak-dependent pathway. JAK kinases are not consistently
activated in BCR-ABL-positive cells (69, 70), and activation of STAT5 by BCR-ABL is not blocked by dominant-negative JAK2 mutants (71). BCR-ABL does not associate with Jaks (71) even though its C-terminal region is identical to that of v-Abl (Fig. 1). Subcellular localization and tyrosine kinase activity differ significantly between the two
proteins; the inner plasma membrane localization and/or high tyrosine
kinase activity of v-Abl may be critical for Jak association and
activation. Nevertheless, STAT1 and STAT5 are constitutively activated
in BCR-ABL lines from CML patients (72), and primary peripheral blood
cells from patients with CML have constitutive activation of STATs
(70). Direct association of STAT SH2 domains with phosphorylated
tyrosines on BCR-ABL could mediate Jak-independent activation, but no
data are available to prove this (69, 71).
Other downstream consequences are known to result from the action
of either v-Abl or BCR-ABL, but the signaling paths leading to them are
poorly understood. v-Abl has been reported to stabilize I Both v-Abl and BCR-ABL activate proteasome-dependent
degradation of specific proteins. In 3T3 fibroblasts,
proteasome-dependent degradation of the
cyclin-dependent kinase inhibitor p27Kip occurs
when mitogen-starved or density-arrested cells enter S following v-Abl
activation.4 In CML cells expressing BCR-ABL,
proteasome-dependent degradation of the inhibitory protein
Abi-2 occurs through a Ras-independent pathway (34). Degradation of p27
and Abi-2 may be induced by a common pathway, but this is not yet proven.
v-Abl and BCR-ABL affect the expression of genes that regulate
apoptosis. v-Abl induces bcl-XL mRNA in
pre-mast cells by a PKC-dependent path (62) but causes
up-regulation of Bax in myeloid progenitor cells (75). v-Abl induces
both Bcl-2 and Bcl-XL in preB cells (66), but it remains to
be shown that this is important for transformation. BCR-ABL induces
Bcl-2 mRNA in a Ras-dependent pathway, and Bcl-2 has
been shown to be essential for BCR-ABL-mediated transformation (76,
77).
The numerous signaling pathways activated by v-Abl are summarized
in Fig. 2. The ultimate effect,
transformation or apoptosis, is likely to be determined by the relative
strength of these signals in different cells. There is much left to
learn. With the exception of E2F-dependent genes, few genes
have been identified as functionally important final targets of the
signaling pathways activated by v-Abl and BCR-ABL. Furthermore, no
pathway has been completely characterized and few have been compared in
different cell types. Thus, there are likely to be many more
connections and many more examples of cross-talk and feedback than we
currently understand. There may also be connections that vary in
different types of cells. In addition, it is clear that we have little
understanding of how a single protein, such as p21ras or E2F-1,
may signal multiple downstream effectors and how the relative strength
of signaling to different effectors may be determined.
v-Abl and BCR-ABL activate a remarkably similar set of signaling
pathways including p21ras, Rac, and STATs and
induction of c-myc mRNA. However, there are several
significant differences. BCR-ABL does not activate ERK but v-Abl does,
BCR-ABL does not associate with or activate Jaks but v-Abl does,
BCR-ABL associates directly with Grb2 but v-Abl does not, and BCR-ABL
activates JNK through Ras whereas v-Abl activates JNK through Rac.
It seems likely that the transforming versus apoptotic
activities of v-Abl and BCR-ABL result from a delicate balance between many signaling pathways. Many of these, such as induction of
c-myc and other E2F-dependent genes, degradation
of p27, and activation of JNK, Rac, and PI3K, lead to cell cycle
progression. Other signals such as induction of Bcl-XL and
Bcl-2 provide anti-apoptotic signals. Finally, it is possible that
others, by inducing p19ARF may lead to
p53-dependent cell cycle arrest or apoptosis.
*
This minireview will be reprinted
in the 1999 Minireview Compendium, which
will be available in December, 1999.
2
S. Goff, personal communication.
3
M. Coutts, X. Zou, and K. Calame, unpublished data.
4
X. Zou and K. Calame, unpublished data.
The abbreviations used are:
CML, chronic
myelogenous leukemia;
PI3K, phosphatidylinositol 3-kinase;
IL, interleukin;
PKC, protein kinase C;
STAT, signal transducers and
activators of transcription;
Jak, Janus kinase;
JNK, c-Jun
NH2-terminal kinase;
ERK, extracellular signal-regulated
kinase;
I
MINIREVIEW
Signaling Pathways Activated by Oncogenic Forms of Abl Tyrosine
Kinase*
INTRODUCTION
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
View larger version (11K):
[in a new window]
Fig. 1.
Functional motifs of Abl family protein
tyrosine kinases. SH, Src homology domains;
NLS, nuclear localization signal; DB, DNA-binding
domain; AB, actin-binding domain; ATP, the
ATP-binding site in the kinase domain; Y, the main site of
autophosphorylation; GAG, retroviral Gag domain;
zig-zag line, myristoyl fatty acid; BCR,
breakpoint cluster region sequence; PTK, protein tyrosine
kinase activity; Onc, transformation and tumorigenesis
ability. The domains of v-Abl that associate with Shc, Jak, and Abi
were mapped by direct studies and are indicated by red
bars. The region where Crk, Crkl, Nck, and Grb2 bind to
v-Abl is inferred from studies on c-Abl and BCR-ABL and is indicated by
a blue bar. The region of BCR-ABL that associates
with Grb2 is also shown by a blue bar.
Ras-dependent Pathways Are Critical for v-Abl
Activity
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
/ mice bypass the crisis that characterizes the transition from primary transformant to established, fully malignant cell line (51).
The Rac GTP-binding Protein Is Activated by v-Abl
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
PI3K Is Activated by v-Abl
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
v-Abl Activates Protein Kinase C
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
v-Abl Activates Jak/STAT Pathways
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
Signaling Paths Responsible for Other Effects of v-Abl and BCR-ABL
Are Partially Understood
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
B, thereby
blocking activation of NF-B in preB cells (73). However, the role of
NF-B appears to be different for BCR-ABL. Inhibition of NF-B by a
non-degradable form of IB
showed that NF-B is required for
BCR-ABL-mediated tumorigenicity in nude mice and transformation of
primary bone marrow cells (74). Activation of NF-B in this system is
Ras-dependent.
Perspectives
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
View larger version (23K):
[in a new window]
Fig. 2.
Summary of signaling pathways activated by
v-Abl tyrosine kinase. Yellow rectangles
indicate proteins that have been shown to be required for
v-Abl-dependent transformation. Dashed
lines indicate paths that are inferred for v-Abl from
studies in which the signaling path was activated in response to a
different oncoprotein or a mitogen.
FOOTNOTES
To whom correspondence should be addressed. Tel.: 212-305-3504;
Fax: 212-305-1468; E-mail: KLC1{at}columbia.edu.
ABBREVIATIONS
B, inhibitor of kappa B.
REFERENCES
TOP
INTRODUCTION
Ras-dependent Pathways Are...
The Rac GTP-binding Protein...
PI3K Is Activated by...
v-Abl Activates Protein Kinase...
v-Abl Activates Jak/STAT...
Signaling Paths Responsible for...
Perspectives
REFERENCES
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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E. J. Noronha, K. H. Sterling, and K. L. Calame Increased Expression of Bcl-xL and c-Myc Is Associated with Transformation by Abelson Murine Leukemia Virus J. Biol. Chem., December 19, 2003; 278(51): 50915 - 50922. [Abstract] [Full Text] [PDF]
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C. Selleri, J. P. Maciejewski, N. Montuori, P. Ricci, V. Visconte, B. Serio, L. Luciano, and B. Rotoli Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells Blood, August 15, 2003; 102(4): 1490 - 1498. [Abstract] [Full Text] [PDF]
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L. C. Platanias Map kinase signaling pathways and hematologic malignancies Blood, June 15, 2003; 101(12): 4667 - 4679. [Abstract] [Full Text] [PDF]
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 G. Marcucci, D. Perrotti, and M. A. Caligiuri Understanding the Molecular Basis of Imatinib Mesylate Therapy in Chronic Myelogenous Leukemia and the Related Mechanisms of Resistance: Commentary re: A. N. Mohamed et al., The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations. Clin. Cancer Res., 9: 1333-1337, 2003. Clin. Cancer Res., April 1, 2003; 9(4): 1248 - 1252. [Full Text] [PDF]
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K. S. Smith, J. W. Rhee, and M. L. Cleary Transformation of Bone Marrow B-Cell Progenitors by E2A-HLF Requires Coexpression of BCL-2 Mol. Cell. Biol., November 1, 2002; 22(21): 7678 - 7687. [Abstract] [Full Text] [PDF]
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 L. W. Donaldson, G. Gish, T. Pawson, L. E. Kay, and J. D. Forman-Kay Structure of a regulatory complex involving the Abl SH3 domain, the Crk SH2 domain, and a Crk-derived phosphopeptide PNAS, October 29, 2002; 99(22): 14053 - 14058. [Abstract] [Full Text] [PDF]
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Y. Nakamura, R. J. Grumont, and S. Gerondakis NF-{kappa}B1 Can Inhibit v-Abl-Induced Lymphoid Transformation by Functioning as a Negative Regulator of Cyclin D1 Expression Mol. Cell. Biol., August 1, 2002; 22(15): 5563 - 5574. [Abstract] [Full Text] [PDF]
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S. Oki, A. Limnander, N. N. Danial, and P. B. Rothman Functional involvement of Akt signaling downstream of Jak1 in v-Abl-induced activation of hematopoietic cells Blood, July 18, 2002; 100(3): 966 - 973. [Abstract] [Full Text] [PDF]
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A. Slupianek, G. Hoser, I. Majsterek, A. Bronisz, M. Malecki, J. Blasiak, R. Fishel, and T. Skorski Fusion Tyrosine Kinases Induce Drug Resistance by Stimulation of Homology-Dependent Recombination Repair, Prolongation of G2/M Phase, and Protection from Apoptosis Mol. Cell. Biol., June 15, 2002; 22(12): 4189 - 4201. [Abstract] [Full Text] [PDF]
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A. W. Goetz, H. van der Kuip, R. Maya, M. Oren, and W. E. Aulitzky Requirement for Mdm2 in the Survival Effects of Bcr-Abl and Interleukin 3 in Hematopoietic Cells Cancer Res., October 1, 2001; 61(20): 7635 - 7641. [Abstract] [Full Text] [PDF]
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B. Sun, G. Jiang, M.-A. A. Zaydan, V. F. La Russa, H. Safah, and M. Ehrlich ABL1 Promoter Methylation Can Exist Independently of BCR-ABL Transcription in Chronic Myeloid Leukemia Hematopoietic Progenitors Cancer Res., September 1, 2001; 61(18): 6931 - 6937. [Abstract] [Full Text] [PDF]
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M. A. Morgan, O. Dolp, and C. W. M. Reuter Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling Blood, March 15, 2001; 97(6): 1823 - 1834. [Abstract] [Full Text] [PDF]
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C. W. M. Reuter, M. A. Morgan, and L. Bergmann Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood, September 1, 2000; 96(5): 1655 - 1669. [Abstract] [Full Text] [PDF]
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D. Perrotti, A. Iervolino, V. Cesi, M. Cirinná, S. Lombardini, E. Grassilli, S. Bonatti, P. P. Claudio, and B. Calabretta BCR-ABL Prevents c-Jun-Mediated and Proteasome-Dependent FUS (TLS) Proteolysis through a Protein Kinase Cbeta II-Dependent Pathway Mol. Cell. Biol., August 15, 2000; 20(16): 6159 - 6169. [Abstract] [Full Text]
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W. Li, T. Hyun, M. Heller, A. Yam, L. Flechner, J. H. Pierce, and S. Rudikoff Activation of Insulin-like Growth Factor I Receptor Signaling Pathway Is Critical for Mouse Plasma Cell Tumor Growth Cancer Res., July 1, 2000; 60(14): 3909 - 3915. [Abstract] [Full Text]
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X. Zou, F. Cong, M. Coutts, G. Cattoretti, S. P. Goff, and K. Calame p53 Deficiency Increases Transformation by v-Abl and Rescues the Ability of a C-Terminally Truncated v-Abl Mutant To Induce Pre-B Lymphoma In Vivo Mol. Cell. Biol., January 15, 2000; 20(2): 628 - 633. [Abstract] [Full Text]
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J. Sun, J. Zhao, M. A. Schwartz, J. Y. J. Wang, T. Wiedmer, and P. J. Sims c-Abl Tyrosine Kinase Binds and Phosphorylates Phospholipid Scramblase 1 J. Biol. Chem., July 27, 2001; 276(31): 28984 - 28990. [Abstract] [Full Text] [PDF]
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 E. E. Grevengoed, J. J. Loureiro, T. L. Jesse, and M. Peifer Abelson kinase regulates epithelial morphogenesis in Drosophila J. Cell Biol., December 24, 2001; 155(7): 1185 - 1198. [Abstract] [Full Text] [PDF]
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