| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 277, Issue 14, 11617-11620, April 5, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710
The maintenance of normal cell function and
tissue homeostasis is dependent on the precise regulation of multiple
signaling pathways that control cellular decisions to either
proliferate, differentiate, arrest cell growth, or initiate
programmed cell death (apoptosis). Cancer arises when clones
of mutated cells escape this balance and proliferate inappropriately
without compensatory apoptosis. Many studies have revealed
that the disruption of multiple pathways is required for the
development of cancer. Thus, not only is it critical to understand the
normal function of specific pathways but equally important is an
understanding of how they interconnect to synchronously regulate cell
growth versus apoptosis.
Studies of both oncogenic processes as well as normal cell growth
control have revealed a central role for the pathway controlling the
retinoblastoma tumor suppressor protein (Rb). A number of other cell
regulatory activities, including the c-Myc and Ras proto-oncoproteins,
have also been shown to control not only cell proliferation but also
pathways leading to apoptosis. In this review, we will discuss our
current understanding of the Rb/E2F pathway, the c-Myc
transcription factor, and the Ras signaling molecule, followed by
recent work showing interconnections between these pathways, leading to
a more comprehensive picture of the network controlling the balance
between cellular proliferation and apoptosis.
The retinoblastoma (Rb) gene was the first
identified tumor suppressor gene (1). The Rb protein is now recognized
to be a central component of a signaling pathway that controls cell proliferation. Specifically the D-type G1 cyclins, together
with their associated kinases, Cdk4 and Cdk6, initiate the
phosphorylation of Rb and Rb family members, p130 and p107,
inactivating their capacity to interact with the E2F transcription
factors (Fig. 1). This phosphorylation
allows the accumulation of E2F1, E2F2, and E2F3a that activate the
transcription of a large number of genes essential for DNA replication
as well as further cell cycle progression (2-4). In addition,
phosphorylation of Rb and p130 also disrupts complexes with E2F3b,
E2F4, and E2F5 found in quiescent cells that function as
transcriptional repressors of S phase genes as well as the genes
encoding the E2F1, E2F2, and E2F3a proteins (Fig. 1).
INTRODUCTION
The Rb/E2F Pathway and Cellular Proliferation
View larger version (18K):
[in a new window]
Fig. 1.
The Rb/E2F pathway.
Among the E2F targets are genes encoding a second class of G1 cyclins, cyclin E and the associated kinase Cdk2. E2F activation of cyclin E/Cdk2 kinase activity leads to the further phosphorylation and inactivation of Rb, thus further enhancing E2F activity and increasing the accumulation of cyclin E/Cdk2 (Fig. 1). This feedback loop, leading to a continual inactivation of Rb independent of the action of cyclin D/Cdk4, may represent at least part of the restriction point identified by Pardee and colleagues (5, 6), defined as the juncture in the cell proliferation response when passage through the cell cycle becomes growth factor-independent. Finally, the activity of the G1 Cdks is negatively regulated by a family of small protein inhibitors referred to as CKIs, including p21, p27, and the p16INK4a family (7). Deregulation of many of the proteins that participate in this regulatory pathway, such as loss of the tumor suppressor protein Rb, overexpression of D-type cyclins, or loss of the CKI p16 is an essential step in the development of the majority of human tumors (8).
E2F activity represents a series of heterodimers made up of six
distinct E2F proteins complexed with one of two DP proteins. Various properties of the individual E2F family members suggest distinct functional roles for the proteins. The E2Fs can be classified into three or possibly four subgroups (2, 3). The first group consists
of E2F1, E2F2, and E2F3a, whose expression is regulated by cell growth,
with maximal accumulation at the G1/S boundary. These three
E2Fs associate exclusively with Rb and appear to play a positive role
in cell cycle progression. The next subgroup is composed of E2F4 and
E2F5, which bind all three Rb family members and appear to function in
transcriptional repression in combination with the p130 protein in
G0 and early G1 phase. The E2F4 and E2F5 genes
are not transcriptionally regulated in relation to cell growth. E2F3b,
like E2F4 and E2F5, is constitutively expressed but appears to bind
exclusively to Rb. Finally, E2F6 is in its own group because it lacks
the domains that are involved in transactivation and binding to Rb
family members. E2F6, like E2F4 and E2F5, functions as a repressor of
E2F-dependent transcription.
| |
The Rb/E2F Pathway and Apoptosis |
|---|
The Rb/E2F pathway has also been shown to integrate with pathways that control programmed cell death. Evidence for a role for the Rb/E2F pathway in apoptosis can be seen in Rb-deficient embryos, which show defects in fetal liver hematopoiesis, neurogenesis, and lens development, and in all three tissue types, ectopic S-phase entry and extensive programmed cell death are observed (9, 10). Moreover, E2F1 knockout mice crossed with Rb-deficient mice partially rescue the apoptotic phenotype (11), and ectopic E2F1 expression has been demonstrated to induce apoptosis under conditions where serum growth factors, which normally impart survival signals, are limiting.
The p53 protein plays a key role in cellular decisions to either arrest
the cell cycle, allowing the repair of damaged DNA, or to commit to
cell death (12). p53 accumulation is negatively regulated by Mdm2,
which targets it for ubiquitin-mediated proteasome degradation; Mdm2
is, in turn, negatively regulated by p19ARF (13, 14). E2F1
induces the expression of p19ARF (15), thus directly connecting
the Rb/E2F pathway to p53 accumulation and an apoptotic response (Fig.
2). However, E2F1 can also induce apoptosis in a p53-independent manner, which could be attributed, at
least in part, to the activation of a p53 family member p73 (16, 17).
In addition, E2F1 has been shown to specifically induce expression of
Apafl (18), which in combination with cytosolic cytochrome c
and the caspase 9 protease forms the so-called apoptosome. This
ternary complex then activates the downstream caspase proteases that
are the final effectors of cell death (Fig. 2).
|
Further evidence for a unique role for E2F1 in an apoptotic response is
seen from the observation that E2F1 is specifically induced following
DNA damage (19). p53 is also induced upon DNA damage via the ATM and
ATR protein kinases, which are activated by DNA damage, and then target
p53 directly or indirectly through the Chk2 kinase (20). The
phosphorylation of p53 by ATM/ATR then blocks the ability of Mdm2 to
target p53 destruction. The induction of E2F1 in response to DNA damage
similarly involves the ATM/ATR kinases (21) (Fig. 2), which
phosphorylate E2F1, inhibiting its degradation. The specificity of ATM
and ATR for E2F1, rather than other E2F proteins, reflects a unique
phosphorylation site within the N-terminal domain of E2F1. Presumably,
this induction of E2F1 in response to DNA damage provides for a
synergistic activation of p53 through the activation of p19ARF
or contributes to p53-independent apoptosis, possibly via activation of p73 (Fig. 2).
| |
The c-Myc Transcription Factor |
|---|
A variety of studies demonstrate that tight regulation of Myc protein levels is essential for normal cell function. Myc expression is regulated at multiple levels. myc RNA expression is controlled by both cell growth-associated increases in myc gene transcription and an increase in myc mRNA stability (22). Recent work has demonstrated that Myc protein expression is not only regulated by new synthesis, dependent upon its mRNA levels, but also by cell growth-related changes in Myc protein half-life (23). Specifically, Myc protein is subjected to very rapid degradation in quiescent fibroblasts with a half-life of ~10 min but is dramatically stabilized following serum stimulation and the initiation of cell cycle progression, extending the half-life to ~60 min. The degradation and turnover of Myc protein, as well as many other cell cycle regulatory proteins, including E2F1 and p53, has been shown to occur via the ubiquitin/26 S proteasome pathway. This pathway involves a specific multistep process that results in a polyubiquitinated target protein, which is then rapidly destroyed by the 26 S proteasome (24). In most cases, the multiubiquitination of a target protein is a regulated event, often controlled by posttranslational modification of the target protein.
Similar to the Rb/E2F pathway, Myc expression couples cellular proliferation with the induction of apoptosis under specific growth conditions where survival growth factors are limiting (25, 26). It has been suggested that the ability of Myc to concomitantly induce proliferation and apoptosis provides a mechanism to guard against a single proliferative lesion leading to unrestrained cell growth. Thus, in order for cells to survive with deregulated Myc expression they would require either a continuous supply of survival factors or the acquisition of additional anti-apoptotic mutations. Indeed, lesions in either the p53 pathway or overexpression of Bcl-2 family members that are anti-apoptotic have both been shown to collaborate with Myc for tumor formation in vivo (27, 28). Regions of Myc required for the induction of apoptosis coincide with those needed for cell proliferation and include all the requisite motifs characteristic of a transcription factor (29). Nonetheless, substantial evidence indicates that c-Myc-induced apoptosis and proliferation are discrete downstream programs because activation of the molecular machinery mediating cell cycle progression is not required for c-Myc-induced apoptosis (30).
Myc-induced apoptosis is largely dependent upon p53 signaling and,
similar to E2F1, involves the induction of p19ARF, inhibition
of Mdm2, and elevated p53 expression (31) (Fig. 2). However, it is also evident that Myc
functions as an initiator of apoptosis by sensitizing cells to a wide
variety of apoptotic stimuli, including serum/growth factor
deprivation, p53-dependent response to genotoxic damage,
virus infection, tumor necrosis factor, and CD95/Fas signaling (26).
Recent experiments have demonstrated that Myc-induced sensitization to
apoptotic stimuli is mediated by changes in the mitochondrial membrane
resulting in the release of cytochrome c into the cytoplasm,
and this process can be blocked by survival factors such as
insulin-like growth factor 1 (32) (Fig. 2).
| |
Connecting Myc with the Rb/E2F Pathway |
|---|
A number of target genes for Myc have been identified that could play a role in the action of Myc in cell proliferation control (33). Myc has been shown to induce G1 cyclin-dependent kinase activity by direct transcriptional activation of cyclin D1 and D2, the cyclin D partner Cdk4, and the phosphatase Cdc25A that removes negative regulatory phosphates from the Cdks (Fig. 2). Myc expression also leads to the rapid induction of cyclin E/Cdk2 activity, which in most cases is essential for Myc-induced cellular proliferation (30, 34, 35). Recent experiments have demonstrated that it is the induction of cyclin D1 and D2 by Myc that results in sequestration of the p27 CKI away from cyclin E, leading to its activation (36, 37). Myc expression also strongly down-regulates p27 (30).
Myc overexpression has also been reported to induce E2F DNA binding activity (38). Although this could result from the Myc-mediated induction of cyclin D/Cdk4 and/or cyclin E/Cdk2, leading to the phosphorylation and inactivation of Rb family members and the release of free E2F, recent work has also shown that Myc directly contributes to the activation of the E2F1, E2F2, and E2F3 genes (Fig. 2) (23, 39, 40). Ectopic Myc expression in quiescent fibroblasts induces E2F1, E2F2, and E2F3 mRNA accumulation in the absence of G1 Cdk activity and G1 to S phase progression.
Myc and E2F transcription factors share a number of functional
properties including the ability to induce quiescent cells to enter the
cell cycle and progress into S phase and to control cell fate by
activating the p53-dependent apoptotic pathway. The fact
that Myc and E2F share these functional properties, coupled with the
fact that Myc can induce E2F gene expression, raises the possibility
that Myc function might be mediated, at least in part, through the
action of the E2F transcription factors. This possibility has recently
been addressed using a genetic approach (41). Primary mouse embryo
fibroblasts (MEFs)1 from
embryos deleted for specific E2F genes were used to evaluate the
functional relationship between Myc and various E2F proteins. Experiments using these E2F-deficient MEFs showed that the ability of
Myc to induce S phase in the absence of other mitogens is severely impaired in MEFs deleted for E2F2 or E2F3 but not E2F1 or E2F4. In
contrast, Myc-induced apoptosis in primary serum-deprived MEFs was
dramatically reduced in cells deleted for E2F1 but not affected by E2F2
or E2F3 deletion. In addition, the ability of Myc to induce p53
expression in the absence of survival factors is also dependent upon
the presence of functional E2F1 but not E2F2 or
E2F3.2 Thus, the induction of
specific E2F activities is an essential downstream event in the Myc
pathway that controls cell proliferation versus apoptosis,
and some of the functions of Myc, such as the induction of
p19ARF and p53 could be explained, at least in part, with one
pathway leading through E2F activation (Fig. 2).
| |
Ras Signaling Pathways |
|---|
The ras proto-oncogene plays a critical role in cell growth control as a central component of mitogenic signal transduction pathways (42, 43). Studies on Ras signaling over the past two decades have shown that this complex regulatory activity can stimulate very diverse biological responses such as cell proliferation or growth arrest, senescence or differentiation, and apoptosis or survival (44). Mitogen stimulation results in an increase in the active, GTP-bound form of Ras. Oncogenic activation of Ras, due to point mutations that maintain Ras in the GTP-bound form, occurs in a large number of human cancers (45).
Ras function is carried out by a family of Ras effector molecules,
which specifically bind to and are activated by Ras-GTP. Among the
effector signaling pathways are the Raf/MEK/ERK kinase cascade,
primarily involved in plasma membrane-to-nucleus signaling (46), the
Ral GTPase signaling pathway, also involved in G1 to
S phase progression (47, 48), and the PI3-K/AKT pathway, which
is involved in cell survival signaling (49) (Fig.
3). Although these effector pathways were
originally thought to mediate discrete cell functions, it is now
apparent that there is extensive overlap in their function; and
Ras-mediated phenotypic responses appear to require the combination of
multiple effector pathways (48, 50, 51).
|
A number of cell survival signals, generated in response to growth
factor stimulation, function through the Ras/PI3-K/AKT pathway and
result in the inhibition of cytochrome c release (52). This
may in part be through AKT-mediated phosphorylation and functional inactivation of BAD, a pro-apoptotic Bcl-2 family protein that promotes
the release of cytochrome c by interfering with the
anti-apoptotic activity of Bcl-XL at the mitochondrial membrane (53,
54) (Fig. 3). However, AKT also appears to have a postmitochondrial function in cell survival because even in the presence of released cytochrome c, AKT can inhibit cell death (55). This appears to be a function of AKT-mediated inhibition of caspase-9 and -3 activation, possibly by direct phosphorylation of caspase-9. A recent
report also demonstrates that AKT promotes the translocation of Mdm2
from the cytoplasm to the nucleus, facilitating the targeting of
p53 for destruction (56) (Fig. 3).
| |
Connecting Ras with the Rb/E2F Pathway |
|---|
Activation of Ras signaling pathways has been shown to be essential for cells both to leave a quiescent state and to progress through G1 phase of the cell cycle. Based on experiments in cells expressing wild-type or mutant Rb, the main role for Ras in G1 progression is to inactivate Rb through the activation of G1 Cdks (39, 57). This has been shown to occur through the stimulation of cyclin D1 transcription as well as increases in the level of cyclin D1/Cdk4 kinase activity (58, 59). As depicted in Fig. 3, three Ras effector pathways, the Raf/MEK/ERK cascade, PI3-K signaling, and Ral activation, are all involved in stimulating cyclin D1 gene transcription, with maximal stimulation requiring the cooperative action of several pathways (47). In addition, PI3-K/AKT signaling, via inhibition of glycogen synthase kinase (GSK-3), increases the stability of the cyclin D1 protein (60).
Ras activity also stimulates transcription of the cyclin kinase
inhibitor p21 and p16INK4a, which could underlie the ability of
Ras to induce cellular senescence (61). In contrast, Ras activation has
been shown to down-regulate the p27kip1 CKI, resulting in the
activation of cyclin E/Cdk2 (62). The down-regulation of p27 involves
both the ERK and PI3-K effector signaling pathways, and it is
associated with a decrease in the rate of p27 translation, stability,
and association with cyclin E/Cdk2, and this is essential for
Ras-mediated entry into S phase (63). Ras, via Raf, has also been
reported to activate the Cdc25A phosphatase that removes inhibitory
phosphates from Cdk2 and Cdk4 contributing to their activation (64).
Taken together, these data place Ras upstream of the G1
Cdk/Rb/E2F pathway.
| |
Connecting Ras with Myc |
|---|
One of the classic paradigms of cellular transformation, and the original basis for the multi-hit theory of cancer, is the collaborative effects of Myc and Ras coexpression in primary fibroblasts. Although Myc expression or Ras expression alone can readily transform immortalized cell lines, which have already escaped normal growth arrest check points, coexpression of both Myc and activated Ras is necessary for the transformation of primary or early passage cells as well as some cell lines (65). However, with the complex and diverse signals emanating from Ras, it is not surprising that the molecular mechanisms underlying Myc/Ras collaboration, both for normal cell proliferation and oncogenesis, have remained elusive despite many years of intensive research. One clear mechanism for Ras/Myc collaboration in oncogenesis is the fact that Ras activation can provide a survival signal, via the PI3-K/AKT pathway, and prevent the overexpression of Myc from inducing apoptosis (66). The ability of Ras to protect against Myc-induced apoptosis is key when one thinks about Myc and cancer, because Myc-induced apoptosis can prevent the outgrowth of a cell population, even though Myc is stimulating cell cycle transit.
Myc and Ras collaboration can also be seen by the fact that although high level expression of c-Myc alone results in cellular proliferation, coupled with the induction of cyclin E/Cdk2 kinase activity and the down-regulation of p27 (67, 68), lower levels of Myc do not have this function unless coexpressed with activated Ras (39). One molecular mechanism that is likely to underlie this observation is based on recent experiments, which show that Ras signaling stabilizes and increases the accumulation of functional Myc transcription factor (23). This finding also provides an important mechanism that is likely to underlie Myc/Ras collaboration in oncogenic cell transformation. Indeed, Myc overexpression is sufficient for premalignant and malignant transformation of some cell types in transgenic mouse models (69, 70). As previously discussed, Myc protein levels are controlled by ubiquitin-mediated proteolysis in a cell growth-dependent manner. Further experiments have shown that the serum-induced increase in Myc protein half-life is dependent upon activation of Ras signaling.
As diagrammed in Fig. 3, two Ras effector pathways contribute to the
stabilization of Myc, the Raf/MEK/ERK kinase cascade and the PI3-K/AKT
signaling pathway. These Ras effector pathways control the
phosphorylation of two sites in the N terminus of Myc, which are
conserved between all Myc family members and have opposing effects on
Myc stability (71). Specifically, activation of ERK kinases results in
the direct phosphorylation of serine 62, which stabilizes Myc protein,
and activation of AKT phosphorylates and inactivates GSK-3 that is
responsible for phosphorylation of threonine 58, which destabilizes Myc
and targets it for ubiquitin-mediated degradation. In addition, there
is a hierarchical relationship between these two phosphorylation sites
where phosphorylation of threonine 58 requires prior phosphorylation of
serine 62. Thus, following serum stimulation and entry into the cell
cycle, myc gene transcription is induced, myc
mRNA accumulates, and Myc protein is synthesized. At the same time
Ras activation of ERKs leads to the phosphorylation of the newly
synthesized Myc on serine 62, and activation of AKT down-regulates
GSK-3 inhibiting the destabilizing phosphorylation of threonine 58, thus allowing rapid and high level accumulation of Myc. Then, as the
cell cycle progresses and AKT activity falls, GSK-3 becomes active
leading to the phosphorylation of threonine 58 and the increased
degradation of Myc. As such, Myc protein levels decline later in
G1 and then persist at this low level as a cell continues
to grow. Although this regulation of Myc stability appears complex, it
allows for precise timing and controlled levels of Myc expression.
| |
Alterations in G1 Signaling Pathways in Cancer |
|---|
Lesions in the Rb/E2F, Myc, and Ras pathways occur in virtually
all human tumors described to date (45, 72, 73). As discussed in this
review, each of these pathways plays an important role in the control
of cellular proliferation as well as apoptosis. Moreover, recent
evidence demonstrates that extensive cross-talk exists between these
cell regulatory pathways (see Fig. 3). Specifically, Ras activation
facilitates Myc function by stabilizing Myc protein and at the same
time blocking the pro-apoptotic effects of Myc. Ras activation also
leads to the activation of cyclin D/cdk4 and the Rb/E2F pathway. Myc
activation can also lead to cyclin D/cdk4 and cyclin E/cdk2 activation.
Finally, Myc activation can directly feed into the Rb/E2F pathway by
inducing E2F gene expression; and Myc function, both for proliferation
and apoptosis, is at least in part dependent upon activation of
distinct E2F proteins. It is clear from these recent experiments
demonstrating that extensive networking exists between cellular
pathways controlling proliferation and apoptosis that
understanding how molecular pathways interconnect is essential for
our understanding of the cancer disease process and for the development
of meaningful treatments.
| |
FOOTNOTES |
|---|
* This minireview will be reprinted in the 2002 Minireview Compendium, which will be available in December, 2002.
To whom correspondence should be addressed: Dept. of Genetics,
Howard Hughes Medical Inst., Duke University Medical Center, Box 3054, Durham, NC 27710. Tel.: 919-684-2746; E-mail: j.nevins@duke.edu.
Published, JBC Papers in Press, January 22, 2002, DOI 10.1074/jbc.R100063200
2 R. Sears, unpublished data.
| |
ABBREVIATIONS |
|---|
The abbreviations used are: MEF, mouse embryo fibroblast; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; ERK, extracellular signal-regulated kinase; PI3-K, phosphatidylinositol 3-kinase; GSK, glycogen synthase kinase.
| |
REFERENCES |
|---|
| 1. |
Hanahan, D.,
and Weinberg, R. A.
(2000)
Cell
100,
57-70[CrossRef][Medline]
[Order article via Infotrieve] |
| 2. |
Dyson, N.
(1998)
Genes Dev.
12,
2245-2262 |
| 3. |
Nevins, J. R.
(1998)
Cell Growth & Differ.
9,
585-593[Medline]
[Order article via Infotrieve] |
| 4. |
Harbour, J. W.,
and Dean, D. C.
(2000)
Nat. Cell Biol.
2,
E65-E67[CrossRef][Medline]
[Order article via Infotrieve] |
| 5. |
Dou, Q. P.,
Levin, A. H.,
Zhao, S.,
and Pardee, A. B.
(1993)
Cancer Res.
53,
1493-1497 |
| 6. |
Pardee, A. B.
(1974)
Proc. Natl. Acad. Sci. U. S. A.
71,
1286-1290 |
| 7. |
Sherr, C. J.,
and Roberts, J. M.
(1999)
Genes Dev.
13,
1501-1512 |
| 8. |
Sherr, C. J.
(1996)
Science
274,
1672-1677 |
| 9. |
Macleod, K. F., Hu, Y.,
and Jacks, T.
(1996)
EMBO J.
15,
6178-6188[Medline]
[Order article via Infotrieve] |
| 10. |
Morgenbesser, S. D.,
Williams, B. O.,
Jacks, T.,
and DePincho, R. A.
(1994)
Nature
371,
72-74[CrossRef][Medline]
[Order article via Infotrieve] |
| 11. |
Tsai, K. Y., Hu, Y.,
Macleod, K. F.,
Crowley, D.,
Yamasaki, L.,
and Jacks, T.
(1998)
Mol. Cell
2,
293-304[CrossRef][Medline]
[Order article via Infotrieve] |
| 12. |
Vogelstein, B.,
Lane, D.,
and Levine, A. J.
(2000)
Nature
408,
307-310[CrossRef][Medline]
[Order article via Infotrieve] |
| 13. |
Prives, C.
(1998)
Cell
95,
5-8[CrossRef][Medline]
[Order article via Infotrieve] |
| 14. |
Sherr, C. J.,
and Weber, J. D.
(2000)
Curr. Opin. Genet. Dev.
10,
94-99[CrossRef][Medline]
[Order article via Infotrieve] |
| 15. |
DeGregori, J.,
Leone, G.,
Miron, A.,
Jakoi, L.,
and Nevins, J. R.
(1997)
Proc. Natl. Acad. Sci. U. S. A.
94,
7245-7250 |
| 16. |
Lissy, N. A.,
Davis, P. K.,
Irwin, M.,
Kaelin, W. G.,
and Dowdy, S. F.
(2000)
Nature
407,
642-644[CrossRef][Medline]
[Order article via Infotrieve] |
| 17. |
Irwin, M.,
Martin, M. C.,
Phillips, A. C.,
Seelan, R. S.,
Smith, D. I.,
Liu, W.,
Flores, E. R.,
Tsai, K. Y.,
Jacks, T.,
Vousden, K. H.,
and Kaelin, W. G., Jr.
(2000)
Nature
407,
645-648[CrossRef][Medline]
[Order article via Infotrieve] |
| 18. |
Moroni, M. C.,
Hickman, E. S.,
Denchi, E. L.,
Caprara, G.,
Colli, E.,
Cecconi, F.,
Muller, H.,
and Helin, K.
(2001)
Nat. Cell Biol.
3,
552-558[CrossRef][Medline]
[Order article via Infotrieve] |
| 19. |
Blattner, C.,
Sparks, A.,
and Lane, D.
(1999)
Mol. Cell. Biol.
19,
3704-3713 |
| 20. |
Hirao, A.,
Kong, Y. Y.,
Matsuoka, S.,
Wakeham, A.,
Ruland, J.,
Yoshida, H.,
Liu, D.,
Elledge, S. J.,
and Mak, T. W.
(2000)
Science
287,
1824-1827 |
| 21. |
Lin, W.-C.,
Lin, F.-T.,
and Nevins, J. R.
(2001)
Genes Dev.
15,
1833-1845 |
| 22. |
Jones, T. R.,
and Cole, M. D.
(1987)
Mol. Cell. Biol.
7,
4513-4521 |
| 23. |
Sears, R.,
Leone, G.,
DeGregori, J.,
and Nevins, J. R.
(1999)
Mol. Cell
3,
169-179[CrossRef][Medline]
[Order article via Infotrieve] |
| 24. |
Hershko, A.,
and Ciechanover, A.
(1998)
Annu. Rev. Biochem.
67,
425-479[CrossRef][Medline]
[Order article via Infotrieve] |
| 25. |
Evan, G.,
and Littlewood, T.
(1998)
Science
281,
1317-1322 |
| 26. |
Prendergast, G. C.
(1999)
Oncogene
18,
2967-2987[CrossRef][Medline]
[Order article via Infotrieve] |
| 27. |
Strasser, A.,
Harris, A. W.,
Bath, M. L.,
and Cory, S.
(1990)
Nature
348,
331-333[CrossRef][Medline]
[Order article via Infotrieve] |
| 28. |
Elson, A.,
Deng, C.,
Campos-Torres, J.,
Donehower, L. A.,
and Leder, P.
(1995)
Oncogene
11,
181-190[Medline]
[Order article via Infotrieve] |
| 29. |
Evan, G. L.,
Wyllie, A. H.,
Gilbert, C. S.,
Littlewood, T. D.,
Land, H.,
Brooks, M.,
Waters, C. M.,
Penn, L. Z.,
and Hancock, D. C.
(1992)
Cell
69,
119-128[CrossRef][Medline]
[Order article via Infotrieve] |
| 30. |
Rudolph, B.,
Saffrich, R.,
Zwicker, J.,
Henglein, B.,
Muller, R.,
Ansorge, W.,
and Eilers, M.
(1996)
EMBO J.
15,
3065-3076[Medline]
[Order article via Infotrieve] |
| 31. |
Zindy, F.,
Eischen, C. M.,
Randle, D. H.,
Kamijo, T.,
Cleveland, J. L.,
Sherr, C. J.,
and Roussel, M. F.
(1998)
Genes Dev.
12,
2424-2433 |
| 32. |
Juin, P.,
Hueber, A. O.,
Littlewood, T.,
and Evan, G.
(1999)
Genes Dev.
13,
1367-1381 |
| 33. |
Dang, C. V.
(1999)
Mol. Cell. Biol.
19,
1-11 |
| 34. |
Santoni-Rugiu, E.,
Falck, J.,
Mailand, N.,
Bartek, J.,
and Lukas, J.
(2000)
Mol. Cell. Biol.
20,
3497-3509 |
| 35. |
Beier, R.,
Burgin, A.,
Kiermaier, A.,
Fero, M.,
Karsunky, H.,
Saffrich, R.,
Moroy, T.,
Ansorge, W.,
Roberts, J.,
and Eilers, M.
(2000)
EMBO J.
19,
5813-5823[CrossRef][Medline]
[Order article via Infotrieve] |
| 36. |
Perez-Roger, I.,
Kim, S.-H.,
Griffiths, B.,
Sewing, A.,
and Land, H.
(1999)
EMBO J.
18,
5310-5320[CrossRef][Medline]
[Order article via Infotrieve] |
| 37. |
Bouchard, C.,
Thieke, K.,
Maier, A.,
Saffrich, R.,
Hanley-Hyde, J.,
Ansorge, W.,
Reed, S.,
Sicinski, P.,
Bartek, J.,
and Eilers, M.
(1999)
EMBO J.
18,
5321-5333[CrossRef][Medline]
[Order article via Infotrieve] |
| 38. |
Jansen-Durr, P.,
Meichle, A.,
Steiner, P.,
Pagano, M.,
Finke, K.,
Botz, J.,
Wessbecher, J.,
Draetta, G.,
and Eilers, M.
(1993)
Proc. Natl. Acad. Sci. U. S. A.
90,
3685-3689 |
| 39. |
Leone, G.,
DeGregori, J.,
Sears, R.,
Jakoi, L.,
and Nevins, J. R.
(1997)
Nature
387,
422-426[CrossRef][Medline]
[Order article via Infotrieve] |
| 40. |
Adams, M. R.,
Sears, R.,
Nuckolls, F.,
Leone, G.,
and Nevins, J. R.
(2000)
Mol. Cell. Biol.
20,
3633-3639 |
| 41. |
Leone, G.,
Sears, R.,
Huang, E.,
Rempel, R.,
Nuckolls, F.,
Park, C.-H.,
Giangrande, P., Wu, L.,
Saavedra, H.,
Field, S. J.,
Thompson, M. A.,
Yang, H.,
Fujiwara, Y.,
Greenberg, M. E.,
Orkin, S.,
Smith, C.,
and Nevins, J. R.
(2001)
Mol. Cell
8,
105-113[CrossRef][Medline]
[Order article via Infotrieve] |
| 42. |
White, M. A.,
Nicolette, C.,
Minden, A.,
Polverino, A.,
Van Aeist, L.,
Karin, M.,
and Wigler, M. H.
(1995)
Cell
80,
533-541[CrossRef][Medline]
[Order article via Infotrieve] |
| 43. |
Marshall, C. J.
(1996)
Curr. Opin. Cell Biol.
8,
197-204[CrossRef][Medline]
[Order article via Infotrieve] |
| 44. |
Frame, S.,
and Balmain, A.
(2000)
Curr. Opin. Genet. Dev.
10,
106-113[CrossRef][Medline]
[Order article via Infotrieve] |
| 45. |
Barbacid, M.
(1987)
Annu. Rev. Biochem.
56,
779-827[CrossRef][Medline]
[Order article via Infotrieve] |
| 46. |
Seger, R.,
and Krebs, E. G.
(1995)
FASEB J.
9,
726-735[Abstract] |
| 47. |
Marshall, C.
(1999)
Curr. Opin. Cell Biol.
11,
732-736[CrossRef][Medline]
[Order article via Infotrieve] |
| 48. |
Gille, H.,
and Downward, J.
(1999)
J. Biol. Chem.
274,
22033-22040 |
| 49. |
Kennedy, S. G.,
Wagner, A. J.,
Conzen, S. D.,
Jordan, J.,
Bellacosa, A.,
Tsichlis, P. N.,
and Hay, N.
(1997)
Genes Dev.
11,
701-713 |
| 50. |
Campbell, S. L.,
Khosravi-Far, R.,
Rossman, K. L.,
Clark, G. J.,
and Der, C. J.
(1998)
Oncogene
17,
1395-1413[CrossRef][Medline]
[Order article via Infotrieve] |
| 51. |
Downward, J.
(1998)
Curr. Opin. Genet. Dev.
8,
49-54[CrossRef][Medline]
[Order article via Infotrieve] |
| 52. |
Kennedy, S. G.,
Kandel, E. S.,
Cross, T. K.,
and Hay, N.
(1999)
Mol. Cell. Biol.
19,
5800-5810 |
| 53. |
Datta, S. R.,
Dudek, H.,
Tao, X.,
Masters, S., Fu, H.,
Gotoh, Y.,
and Greenberg, M. E.
(1997)
Cell
91,
231-241[CrossRef][Medline]
[Order article via Infotrieve] |
| 54. |
del Peso, L.,
Gonzalez-Garcia, M.,
Page, C.,
Herrera, R.,
and Nunez, G.
(1998)
Science
278,
687-689 |
| 55. |
Zhou, H., Li, X.-M.,
Meinkoth, J.,
and Pittman, R. N.
(2000)
J. Cell Biol.
151,
483-493 |
| 56. |
Mayo, L. D.,
and Donner, D. B.
(2001)
Proc. Natl. Acad. Sci. U. S. A.
98,
11598-11603 |
| 57. |
Peeper, D. S.,
Upton, T. M.,
Ladha, M. H.,
Neuman, E.,
Zalvide, J.,
Bernards, R.,
DeCaprio, J. A.,
and Ewen, M. E.
(1997)
Nature
386,
177-181[CrossRef][Medline]
[Order article via Infotrieve] |
| 58. |
Liu, J.-J.,
Chao, J.-R.,
Jiang, M.-C., Ng, S.-Y.,
Yen, J. J. Y.,
and Yang-Yen, H.-F.
(1995)
Mol. Cell. Biol.
15,
3654-3663[Abstract] |
| 59. |
Robles, A. I.,
Rodriguez-Puebla, M. L.,
Glick, A. B.,
Trempus, C.,
Hansen, L.,
Sicinski, P.,
Tennant, R. W.,
Weinberg, R. A.,
Yuspa, S. H.,
and Conti, C. J.
(1998)
Genes Dev.
12,
2469-2474 |
| 60. |
Diehl, J. A.,
Cheng, M.,
Roussel, M. F.,
and Sherr, C. J.
(1998)
Genes Dev.
12,
3499-3511 |
| 61. |
Olson, M. F.,
Paterson, H. F.,
and Marshall, C. J.
(1998)
Nature
394,
295-299[CrossRef][Medline]
[Order article via Infotrieve] |
| 62. |
Aktas, H.,
Cai, H.,
and Cooper, G. M.
(1997)
Mol. Cell. Biol.
17,
3850-3857[Abstract] |
| 63. |
Takuwa, N.,
and Takuwa, Y.
(1997)
Mol. Cell. Biol.
17,
5348-5358[Abstract] |
| 64. |
Galaktionov, K.,
Jessus, C.,
and Beach, D.
(1995)
Genes Dev.
9,
1046-1058 |
| 65. |
Land, H.,
Parada, L. F.,
and Weinberg, R. A.
(1983)
Nature
304,
596-602[CrossRef][Medline]
[Order article via Infotrieve] |
| 66. |
Kauffmann-Zeh, A.,
Rodriquez-Viciana, P.,
Elrich, E.,
Gilbert, C.,
Coffer, P.,
Downward, J.,
and Evan, G.
(1997)
Nature
385,
544-548[CrossRef][Medline]
[Order article via Infotrieve] |
| 67. |
Perez-Roger, I.,
Solomon, D. L. C.,
Sewing, A.,
and Land, H.
(1997)
Oncogene
14,
2373-2381[CrossRef][Medline]
[Order article via Infotrieve] |
| 68. |
Steiner, P.,
Philipp, A.,
Lukas, J.,
Godden-Kent, D.,
Pagano, M.,
Mittnacht, S.,
Bartek, J.,
and Eilers, M.
(1995)
EMBO J.
14,
4814-4826[Medline]
[Order article via Infotrieve] |
| 69. |
Felsher, D. W.,
and Bishop, J. M.
(1999)
Mol. Cell
4,
199-207[CrossRef][Medline]
[Order article via Infotrieve] |
| 70. |
Pelengaris, S.,
Littlewood, T.,
Khan, M.,
Elia, G.,
and Evan, G.
(1999)
Mol. Cell
3,
565-577[CrossRef][Medline]
[Order article via Infotrieve] |
| 71. |
Sears, R.,
Nuckolls, F.,
Haura, E.,
Taya, Y.,
Tamai, K.,
and Nevins, J. R.
(2000)
Genes Dev.
14,
2105-2114 |
| 72. |
Nevins, J. R.
(2001)
Hum. Mol. Genet.
10,
699-703 |
| 73. |
Nesbit, C. E.,
Tersak, J. M.,
and Prochownik, E. V.
(1999)
Oncogene
18,
3004-3016[CrossRef][Medline]
[Order article via Infotrieve] |
This article has been cited by other articles:
|
|
 |
|
  J. Miki, Y.-i. Fujimura, H. Koseki, and T. Kamijo Polycomb complexes regulate cellular senescence by repression of ARF in cooperation with E2F3. Genes Cells, December 1, 2007; 12(12): 1371 - 1382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Byrnes, B. A. Stoica, S. Fricke, S. Di Giovanni, and A. I. Faden Cell cycle activation contributes to post-mitotic cell death and secondary damage after spinal cord injury Brain, November 1, 2007; 130(11): 2977 - 2992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Magnusson, R. Ehrnstrom, J. Olsen, and A. Sjolander An Increased Expression of Cysteinyl Leukotriene 2 Receptor in Colorectal Adenocarcinomas Correlates with High Differentiation Cancer Res., October 1, 2007; 67(19): 9190 - 9198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Opavsky, S.-Y. Tsai, M. Guimond, A. Arora, J. Opavska, B. Becknell, M. Kaufmann, N. A. Walton, J. A. Stephens, S. A. Fernandez, et al. Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis PNAS, September 25, 2007; 104(39): 15400 - 15405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Michod and C. Widmann TAT-RasGAP317-326 Requires p53 and PUMA to Sensitize Tumor Cells to Genotoxins Mol. Cancer Res., May 1, 2007; 5(5): 497 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Biliran Jr., S. Banerjee, A. Thakur, F. H. Sarkar, A. Bollig, F. Ahmed, J. Wu, Y. Sun, and J. D. Liao c-Myc Induced Chemosensitization Is Mediated by Suppression of Cyclin D1 Expression and Nuclear Factor-{kappa}B Activity in Pancreatic Cancer Cells Clin. Cancer Res., May 1, 2007; 13(9): 2811 - 2821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Blum, R. Elkon, S. Yaari, A. Zundelevich, J. Jacob-Hirsch, G. Rechavi, R. Shamir, and Y. Kloog Gene Expression Signature of Human Cancer Cell Lines Treated with the Ras Inhibitor Salirasib (S-Farnesylthiosalicylic Acid) Cancer Res., April 1, 2007; 67(7): 3320 - 3328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Shibuya, H. Okamoto, T. Nozawa, J. Utsumi, V. N. Reddy, H. Echizen, Y. Tanaka, and T. Iwata Proteomic and Transcriptomic Analyses of Retinal Pigment Epithelial Cells Exposed to REF-1/TFPI-2 Invest. Ophthalmol. Vis. Sci., February 1, 2007; 48(2): 516 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, A. Dutuor, L. Tao, X. Fu, and X. Zhang Virotherapy with a Type 2 Herpes Simplex Virus-Derived Oncolytic Virus Induces Potent Antitumor Immunity against Neuroblastoma Clin. Cancer Res., January 1, 2007; 13(1): 316 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Mitra, R. H. Datar, and R. J. Cote Molecular Pathways in Invasive Bladder Cancer: New Insights Into Mechanisms, Progression, and Target Identification J. Clin. Oncol., December 10, 2006; 24(35): 5552 - 5564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. I. Zeller, X. Zhao, C. W. H. Lee, K. P. Chiu, F. Yao, J. T. Yustein, H. S. Ooi, Y. L. Orlov, A. Shahab, H. C. Yong, et al. Global mapping of c-Myc binding sites and target gene networks in human B cells PNAS, November 21, 2006; 103(47): 17834 - 17839. [Abstract] [Full Text] |
TOP
INTRODUCTION
The Rb/E2F Pathway and...
