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Special Lecture |
Howard Hughes Medical Institute and Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105
ABSTRACT
Genetic lesions that disable key regulators of G1 phase progression in mammalian cells are present in most human cancers. Mitogen-dependent, cyclin D-dependent kinases (cdk4 and cdk6) phosphorylate the retinoblastoma (Rb) tumor suppressor protein, helping to cancel its growth-inhibitory effects and enabling E2F transcription factors to activate genes required for entry into the DNA synthetic phase (S) of the cell division cycle. Among the E2F-responsive genes are cyclins E and A, which combine with and activate cdk2 to facilitate S phase entry and progression. Accumulation of cyclin D-dependent kinases during G1 phase sequesters cdk2 inhibitors of the Cip/Kip family, complementing the effects of the E2F transcriptional program by facilitating cyclin E-cdk2 activation at the G1-S transition. Disruption of "the Rb pathway" results from direct mutational inactivation of Rb function, by overexpression of cyclin D-dependent kinases, or through loss of p16INK4a, an inhibitor of the cyclin D-dependent kinases. Reduction in levels of p27Kip1 and increased expression of cyclin E also occur and carry a poor prognostic significance in many common forms of cancer. The ARF tumor suppressor, encoded by an alternative reading frame of the INK4a-ARF locus, senses "mitogenic current" flowing through the Rb pathway and is induced by abnormal growth promoting signals. By antagonizing Mdm2, a negative regulator of the p53 tumor suppressor, ARF triggers a p53-dependent transcriptional response that diverts incipient cancer cells to undergo growth arrest or apoptosis. Although ARF is not directly activated by signals that damage DNA, its loss not only dampens the p53 response to abnormal mitogenic signals but also renders tumor cells resistant to treatment by cytotoxic drugs and irradiation. Lesions in the p16 — cyclin D-CDK4 — Rb and ARF — Mdm2 — p53 pathways occur so frequently in cancer, regardless of patient age or tumor type, that they appear to be part of the life history of most, if not all, cancer cells.
Introduction
"The greatest single achievement of nature to date was surely the invention of the molecule of DNA. We have had it from the very beginning, built into the first cell to emerge, membranes and all, somewhere in the soupy water of the cooling planet three thousand million years or so ago. All of today’s DNA, strung through all of the cells of the earth, is simply an extension and elaboration of that first molecule. In a fundamental sense, we cannot claim to have made progress, since the method used for growth and replication is essentially unchanged" (1) .
As the late Lewis Thomas implied, the principle task of the cell
division cycle is to replicate DNA (without errors during S phase) and
to segregate the duplicated chromosomal DNA equally to two daughter
cells [during mitosis (or M phase)] (Fig. 1
). In addition to the molecular regulators that drive these processes, a
monitoring circuitry ensures that S phase is completed before mitosis
begins and vice versa. Early embryonic cell cycles exhibit
rapidly alternating S and M phases without gap phases between them.
This suggests that the gap phases seen in somatic cell
cycles–G1 separating the M and S phases, and
G2 separating the S and M phases–are not
strictly essential for the correct operation of the cell cycle engine.
It is intriguing to reflect on this point, because many of the
G1 phase regulators that prove so important in
accelerating or braking the cell cycle engine of mammalian cells are
encoded by nonessential genes, whose elimination from the germ line
needs not lead to deleterious effects on organismal development.
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). When cells are stimulated by growth
factors to enter the cycle from G0, they
generally require continuous mitogenic stimulation to be driven to the
restriction point, after which mitogens can be withdrawn and cells will
enter S phase and complete the cycle in their absence. Conversely,
antiproliferative compounds, such as cytokines like transforming growth
factor-ß or drugs such as rapamycin, can only arrest the
proliferation of cells that are progressing through
G1 phase but have not yet reached the restriction
point. In mammalian cells, progression through the restriction point
involves a series of events that lead to, but are distinct from, the
firing of replication origins and that temporally precede the
G1-S transition by several hours (Fig. 1)
. G1 Cyclins and cdks
In general, cell cycle transitions are controlled by cdks.2 These holoenzymes contain both regulatory (cyclin) and catalytic (cdk) subunits but likely exist as higher order complexes that include additional proteins (see below). Restriction point control is mediated by two families of enzymes, the cyclin D- and E-dependent kinases. The D-type cyclins (D1, D2, and D3; Refs. 3–5 ) interact combinatorially with two distinct catalytic partners (cdk4 and cdk6; Refs. 6 and 7 ) to yield at least six possible holoenzymes that are expressed in tissue-specific patterns. Whereas cdk4 and cdk6 are relatively long-lived proteins, the D-type cyclins are unstable, and their induction, synthesis, and assembly with their catalytic partners all depend upon persistent mitogenic signaling. In this sense, the D-type cyclins act as growth factor sensors, forming active kinases in response to extracellular cues (reviewed in Ref. 8 ).
The mitogen-dependent accumulation of the cyclin D-dependent kinases
triggers the phosphorylation of Rb, thereby helping to cancel its
growth-repressive functions (6, 9, 10)
. Rb represses the
transcription of genes whose products are required for DNA synthesis.
It does so by binding transcription factors such as the E2Fs (reviewed
in Ref. 11
) and recruiting repressors such as histone
deacetylases (12–14)
and chromosomal remodeling
SWI/SNF complexes (15)
to E2F-responsive promoters
on DNA. However, Rb phosphorylation by the G1
cdks disrupts these interactions (15, 16)
, enabling
untethered E2Fs to function as transcriptional activators (Fig. 2
). Apart from a battery of genes that regulate DNA metabolism, E2Fs
induce the cyclin E and A genes. Cyclin E enters into a complex with
its catalytic partner cdk2 (17–20)
and collaborates with
the cyclin D-dependent kinases to complete Rb phosphorylation (Fig. 2
;
Refs. 21–26
). This shift in Rb phosphorylation from
mitogen-dependent cyclin D-cdk4/6 complexes to mitogen-independent
cyclin E-cdk2 accounts in part for the loss of dependency on
extracellular growth factors at the restriction point. Cyclin E-cdk2
also phosphorylates substrates other than Rb, and its activity is
somehow linked to replication origin firing (27, 28)
. The
activity of the cyclin E-cdk2 complex peaks at the
G1-S transition, after which cyclin E is degraded
and replaced by cyclin A (Fig. 1)
.
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The actions of cdk2 are opposed by the Cip/Kip family
of polypeptide inhibitors that includes p21Cip1
(29–31)
, p27Kip1
(32–34)
, and p57Kip2 (Refs.
35
and 36
; reviewed in Ref. 37
;
Fig. 1
). In quiescent cells, the levels of
p27Kip1 are generally high. However, as cells
enter cycle and accumulate cyclin D-dependent kinases, the Cip/Kip
proteins are sequestered in complexes with cyclin D-dependent cdks
(Fig. 2)
. Although it was initially assumed that the Cip/Kip proteins
would inhibit both cdk4/6 and cdk2, we now recognize that the
Cip/Kip-bound cyclin D-dependent enzymes remain catalytically active
(38–41)
. Even more surprisingly, it turns out that
Cip/Kip proteins are required for the assembly of the active cyclin
D-dependent holoenzymes (Refs. 40
and 41
;
Fig. 2
). In cycling cells, virtually all of the
p27Kip1 molecules remain associated with cyclin
D-cdk complexes. However, mouse embryo fibroblasts taken from animals
lacking both the Kip1 and Cip1
genes–p57Kip2 is not synthesized in these
cells–express no detectable cyclin D-dependent kinase activity and
still have relatively unperturbed cell cycle transit times
(41)
. In this setting, the levels of cyclin E-cdk2
activity are greatly increased and are apparently sufficient to
phosphorylate Rb. Together, these data point to a second noncatalytic
role of the cyclin D-dependent kinases, i.e., the
mitogen-dependent accumulation of cyclin
D-dependent kinases sequesters Cip/Kip proteins,
thereby facilitating cyclin E-cdk2 activation (reviewed in Ref.
42
). This complements the Rb-E2F transcriptional program
(see above) and helps make the appearance of cyclin E-cdk2 activity
contingent upon accumulation of cyclin D-cdk4/6-Cip/Kip complexes (Fig. 2)
.
Once cyclin E-cdk2 is activated, it phosphorylates
p27Kip1. This converts
p27Kip1 to a form that is recognized by ubiquitin
ligases and is targeted for destruction in proteasomes
(43–47)
. Therefore, cyclin E-cdk2 antagonizes the action
of its own inhibitor (Fig. 2)
. It follows that once cyclin E-cdk2 is
activated, unbound p27Kip1 is rapidly degraded,
contributing to the irreversibility of passage through the restriction
point. If cells are persistently stimulated with mitogens, cyclin
D-dependent kinase activity remains high in subsequent cycles,
p27Kip1 levels stay low, and virtually all of the
p27Kip1 can be found in complexes with the cyclin
D-cdks. However, when mitogens are withdrawn, cyclin D is rapidly
degraded, and previously sequestered Cip/Kip proteins are mobilized to
inhibit cyclin E-cdk2, thereby arresting progression usually within a
single cycle.
The Kip1 gene was not initially thought to be a tumor suppressor, because both copies of the gene were not found to be deleted or silenced in tumor cells. Yet, there is now compelling evidence that Kip1 is haplo-insufficient for tumor suppression, with loss of only one copy of the gene being sufficient to contribute to cancer (48) . In retrospect, we might rationalize this finding through the realization that Cip/Kip proteins are essential for the formation of cyclin D-dependent holoenzymes, although, at least experimentally, p21Cip1 can functionally replace p27Kip1 in this regard. Still, low levels of p27Kip1 (which can be associated with monoallelic Kip1 deletions in tumor cells) combined with high levels of cyclin E are generally indicative of reduced long-term survival in various forms of cancer. This has been well documented in breast cancer, where the levels of p27Kip1 and cyclin E in primary tumors have greater prognostic power than other markers (49, 50) . It is particularly important in women without apparent lymph node involvement, in whom the choice of therapy critically depends on strongly predictive markers of this type.
Cdk Inhibitors: The INK4 Family
Another class of cdk inhibitors, the so-called INK4 proteins
(named for their ability to inhibit cdk4),
specifically target the cyclin D-dependent kinases (reviewed in Refs.
37
and 51
; Fig. 1
). INK4 proteins sequester
cdk4/6 into binary cdk-INK4 complexes, liberating bound Cip/Kip
proteins, and thereby indirectly inhibiting cyclin E-cdk2 to ensure
cell cycle arrest (reviewed in Ref. 42
). The ability of
INK4 proteins to arrest the cell cycle in G1
phase depends upon the presence of a functional Rb protein, implying
that by inhibiting cyclin D-dependent kinases, Rb remains
hypophosphorylated and able to repress transcription of S-phase genes
(52–54)
. Note that disruption of cyclin D-cdk complexes
and release of bound Cip/Kip proteins is insufficient to inhibit cyclin
E-cdk2 in Rb-negative cells. This is likely attributable to the fact
that cyclin E-cdk2 activity is normally under Rb-E2F control (Fig. 2)
,
so that cells lacking Rb exhibit greatly elevated cyclin E-cdk2 kinase
activity. This enables a conceptually simplified view of the "Rb
pathway": INK4 proteins — cyclin D-dependent kinases —
Rb — E2Fs 
S phase entry.
To date, four INK4 proteins have been identified. These include the founding member p16INK4a (55) and three other closely related genes designated p15INK4b (56) , p18INK4c (52, 57) , and p19INK4d (57, 58) . In humans, INK4a and INK4b are closely linked on the short arm of chromosome 9 (59) , whereas INK4c maps to chromosome 1 and INK4d maps to chromosome 19. In mice, the INK4c and INK4d genes are expressed in stereotypic patterns in different tissues during development in utero, whereas INK4a and INK4b expression has not been detected prenatally (60) . Gene disruption experiments in mice have revealed no overt effects of INK4b or INK4d loss (61) . In contrast, mice lacking INK4c are similar to those lacking Kip1 in the sense that they have organomegaly and pituitary tumors (62) . "Pure" INK4a-null mice have not yet been produced (see below). However, one report has provided evidence that inbred BALB/c mice contain defective INK4a alleles that encode p16INK4a proteins incapable of inhibiting cyclin D-dependent kinases (63) . At face value, the collective data argue that disabling single INK4 family members does not particularly increase the rate of spontaneous tumor development in mice.
Nonetheless, there is compelling evidence that INK4a
loss-of-function occurs frequently in human cancers (reviewed in Ref.
51
). In some familial melanomas, for example, one
defective copy of INK4a is inherited, whereas the second is
lost in tumor cells, the reduction to homozygosity being a classic
feature of a tumor suppressor gene (59)
. In many forms of
sporadic cancer, INK4a function is also lost
(51)
. For example, virtually all pancreatic carcinomas
exhibit INK4a defects. As might be expected, the loss of
INK4a represents only one of several ways in which the Rb
pathway can be disabled. In glioblastomas, CDK4 is frequently
amplified, and INK4a function is lost in other cases. In
small cell lung cancer, 
85% of tumors sustain Rb loss, whereas the
remaining tumors exhibit INK4a loss-of function (10%) or
cyclin D amplification (5%; reviewed in Refs. 51
and
64
). A remaining puzzle is why other members of the INK4
gene family are not similarly targeted in human tumors. It therefore
seems that INK4a plays a special role in tumor surveillance
in humans. Whatever the reason for the preferential involvement of
p16INK4a, the available data have led to the
reasonable speculation that disruption of the Rb pathway is part of the
life history of many, if not all, human tumor cells (reviewed in Ref.
64
).
The ARF Tumor Suppressor
Surprisingly, the INK4a gene encodes a second
potent tumor suppressor (65, 66)
. The sequences encoding
p16INK4a are embodied in three exons (designated
1
, 2, and 3), which specify an mRNA transcript of 1 kb. In the
human and mouse genomes, an alternative first exon (designated 1ß)
lies 15–20 kb upstream of the p16INK4a coding
sequences, and its RNA is spliced to the exon 2 and exon 3 RNA segments
to yield a second 1 kb "ß mRNA" whose 5' end differs from the
transcript (65, 67–69)
. Alternative promoters located
5' of exons 1 and 1ß govern the independent production of the two
mRNAs. The unusual feature is that the initiation codons within exons
1 and 1ß are in different reading frames and, when spliced to the
same sequences in exon 2, encode two distinct proteins that bear no
relationship to one another (65)
. In the mouse, the ARF
protein is represented by 64 amino acids encoded by exon 1ß and 105
amino acids specified by exon 2. Mouse p19ARF is
a highly basic protein that, when overexpressed, can cause cell cycle
arrest in both the G1 and
G2 phases of the cell cycle (65)
.
Its human counterpart (p14ARF) contains fewer
exon 2-coded amino acids and is of lower molecular mass, but it has the
same ability to induce cell cycle arrest.
Mice containing disrupted INK4a/ARF exon 2 sequences (70) or lacking only the ARF exon 1ß sequences (66) are highly tumor prone and die of cancers within 15 months of age. The most predominant tumors are sarcomas, followed by lymphomas, carcinomas, and tumors of the central nervous system (71) . ARF+/- heterozygotes develop tumors after a considerably longer latency, and the tumor cells lose the wild-type ARF allele, as is characteristic of a classical tumor suppressor gene. When MEFs of INK4a/ARF or ARF-null animals are explanted into culture and passaged on a defined 3T3 protocol, the cells do not senesce but rather continue to proliferate as established cell lines (66, 70) . Normally, primary MEFs are generally resistant to transformation by oncogenic Ras and require the introduction of a so-called immortalizing oncogene, such as adenovirus E1A or Myc, to undergo transformation (72, 73) . However, like established rodent fibroblast lines, ARF-null cells can be transformed by oncogenic Ras alone (66, 70) . In these respects, ARF-null MEFs are similar to p53-deficient mouse fibroblasts, which are also immortal and can be transformed by Ras without a requirement for Myc or E1A. Moreover, spontaneously immortalized cells derived from a 3T3 protocol contain either mutations in the p53 gene (80%) or exhibit bi-allelic ARF loss (the remaining 20%; Refs. 66 and 74 ). Together, these data suggested that ARF and p53 functioned in the same biochemical pathway.
p53 is a homotetrameric transcription factor that induces either
cell cycle arrest or apoptosis, depending on the biological setting
(reviewed in Refs. 75
and 76
). Introduction
of ARF into cells results in p53-dependent cell cycle
arrest, indicating that ARF acts "upstream" of p53
(66)
. Cells lacking p53 alone are refractory to
ARF-induced arrest, and in this setting, ARF protein expression is
greatly increased. This suggests that p53 suppresses ARF
expression through negative feedback, and consistent with this
interpretation, reintroduction of p53 into these cells returns ARF
protein expression to lower levels (Refs. 77
and
78
; Fig. 3
). ARF stabilizes p53 by antagonizing the p53-negative regulator Mdm2
(77–80)
. Mdm2 binds to the transactivation domain of the
p53 tetramer to inhibit p53-dependent gene expression (81, 82)
, and it also manifests a ubiquitin ligase activity that
appears to target p53 for proteasomal degradation (83)
.
Intriguingly, Mdm2 is itself a p53-responsive gene that normally acts
in feedback control to terminate the p53 response (Refs.
84
and 85
; Fig. 3
). ARF can interfere with
all of the known functions of Mdm2, including its ability to:
(a) block p53 transcription (77–79)
;
(b) to ubiquinate p53 (86)
; and (c)
to enforce p53 transport into the cytoplasm (87–89)
,
where it is degraded in proteasomes (90–92)
.
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ARF expression is activated by abnormal mitogenic signals induced
by overexpression of oncoproteins such as Myc (93)
, E1A
(94)
, E2F1 (95)
, Ras (96)
, and
v-Abl (97)
. In this manner, ARF serves to connect the Rb
pathway with Mdm2 and p53 (Fig. 4
). ARF acts as a fuse to "gate" inappropriate mitogenic signals
flowing through the cyclin D-cdk –Rb –E2F circuit, inducing p53 under
conditions in which abnormal proliferative signals are generated. This
mode of cell-autonomous tumor surveillance diverts cells that have
received an oncogenic insult to undergo p53-dependent growth arrest or
apoptosis, thereby preventing incipient cancer cells from emerging as
overt tumors (reviewed in Ref. 98
).
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Studies using animal models support the view that ARF protects cells
against Myc-induced tumorigenesis. Mice bearing an Eµ-Myc
transgene, in which Myc expression is driven by an immunoglobulin heavy
chain enhancer, develop Burkitt-type B cell lymphomas with a mean
latency of 30 weeks, and all die of the disease by 1 year of age
(99)
. In the early stages before overt tumors arise, the
B-cell compartment of these animals exhibits hyperproliferation, which
is balanced by increased apoptosis. When tumors arise, however, the
apoptotic index is greatly diminished (100, 101)
. About
75% of these lymphomas had lesions (p53 or ARF
loss, or Mdm2 overexpression) that disabled the ARF-Mdm2-p53 pathway.
In addition, when Eµ-Myc mice were crossed onto an
ARF+/- background, tumor progression was greatly
accelerated (mean latency, 12 weeks) and 80% of the resulting tumors
had lost the wild-type ARF allele. Even more strikingly, on
an ARF-null (100)
or INK4a-ARF-null
(101, 102) background, Eµ-Myc transgenic
animals all died of highly aggressive lympholeukemias by only 5–6
weeks of age. By contrast, Rb loss of function did not significantly
accelerate Eµ-Myc-induced disease (101)
. Most
tumors that sustain ARF or p53 mutations do not
respond to therapies that can cure mice in earlier stages of lymphoma
development (101)
. Therefore loss of the ability of ARF to
modulate the p53 response connotes a poor prognosis, even in those
tumors retain wild-type p53.
These data imply that by dynamically resetting the effective Mdm2
threshold, ARF reduces the ability of p53 to function in tumor
suppression. Consistent with this view, loss of ARF makes
cells relatively resistant to apoptosis induced by ionizing radiation
or cyclophosphamide (94)
and can sensitize cells to
polyploidy induced by microtubule inhibitors (103)
.
ARF loss, like p53 mutation, can also rescue
cells lacking the Atm gene from undergoing premature
senescence in culture (104)
, indicating that
ARF loss modulates the Atm-dependent DNA damage checkpoint.
Thus, although DNA damage signals do not appear to activate ARF
per se (Fig. 4)
, ARF loss modulates p53 function in such a way as
to diminish its accumulation in response to genotoxic stress.
Although the most parsimonious interpretation is that ARF functions in
a linear pathway by harnessing the ability of Mdm2 to neutralize p53,
there are several reasons to believe that the ARF-Mdm2-p53 pathway has
alternative branch points. One line of argument concerns the feedback
loops, in which p53 can both induce Mdm2 and repress ARF levels (Fig. 3)
. The biochemical basis for these connections remains unclear.
Moreover, in some Myc-induced lymphomas, perturbations were
observed that affected expression of more than one gene in the pathway
(100)
. For example, a significant fraction of lymphomas
exhibited both ARF loss and Mdm2 overexpression, implying
that both genes can contribute independently to tumor formation. One
possibility is that Mdm2 encodes different truncated isoforms, whose as
yet undetermined functions may differ from the full-length molecule. At
least in principle, ARF might act on targets other than Mdm2, and Mdm2
in turn might regulate proteins other than p53 (Fig. 3)
. Indeed, there
are precedents for the latter, based on reported interactions of Mdm2
with other p53 family members (105)
, Rb (106, 107)
, p300 (108)
, and even E2F1 (109)
.
Much more work is required to critically evaluate these possibilities.
Still, it seems evident that disruption of the ARF-Mdm2-p53 pathway
occurs frequently in cancers. In humans, p53 is itself
mutated in >50% of cancers, whereas ARF loss and Mdm2
overexpression occur in a high fraction of the remaining cases. Hence,
disruption of ARF, Mdm2, and p53, like mutations in the
p16INK4a-cyclin D/cdk4-Rb pathway, again seem to
be part of the life history of cancer cells, irrespective of patient
age or tumor type.
ARF: In Search of Biochemical Function
ARF is a highly basic protein that localizes to the nucleolus (65, 79, 89) . When induced or overexpressed, ARF binds to Mdm2 and imports it into the nucleolus, thereby allowing p53 to accumulate in the nucleoplasm (89, 110, 111) . Recently, ARF was found to bind to a central region of Mdm2 to a segment distinct from Mdm2’s nuclear import and export signals, its NH2-terminal p53 binding domain, and the COOH-terminal RING domain, the integrity of which is required for E3 ubiquitin ligase activity (111) . Both the human and mouse ARF proteins contact Mdm2 through two independent binding sites that are separated by spacer elements of different lengths in the two proteins. In mouse p19ARF, the two Mdm2 binding sites cluster in the ARF NH2 terminus within amino acids 1–37 (111) . Segments containing amino acids 1–14 and 26–37 are responsible for cooperative binding and induce an allosteric change in Mdm2 that facilitates its nucleolar import. Interestingly, a cryptic localization signal within the COOH-terminal Mdm2 RING domain contributes to the nuclear import of the ARF-Mdm2 complex. Mutations within this region prevent Mdm2 nucleolar import and instead result in ARF sequestration by Mdm2 in the nucleoplasm (110, 111) . The fact that Mdm2 RING domain mutants can oppose the activity of ARF implies that the ARF-Mdm2 interaction is bidirectional, with each protein having a potential to cancel activities of the other.
Although the spacing between the Mdm2 binding domains in the human p14ARF protein is greater than that in mouse p19ARF (88) , human or mouse ARF mutants that either do not interact properly with Mdm2 or colocalize Mdm2 to the nucleolus are impaired in arresting cell proliferation (89, 110, 111) . To date, these functional data suggest that the ability of ARF to sequester Mdm2 correlates with p53-dependent cell cycle arrest. However, it is formally possible that ARF might also antagonize Mdm2 in the nucleoplasm (88) . These findings raise interesting questions about the in vivo activities of ARF. Is the primary role of ARF to sequester Mdm2 from p53 (89, 110, 111) , to interfere with Mdm2-catalyzed ubiquitination (83) , to prevent Mdm2 from enforcing p53 nuclear export (87–89, 110, 111) , or all of the above?
Conclusions and Future Prospects
In summary, studies over the last decade have indicated that most human cancer cells sustain mutations that affect the functions of Rb and p53, either by disabling these genes directly or by targeting genes that act epistatically to prevent their proper function. The INK4a/ARF locus surprisingly encodes two products that affect both Rb and p53, and the rationale for nature’s design of these overlapping tumor suppressors continues to pose a puzzle. An implication may be that the activities of INK4a and ARF are somehow coregulated through their proximity in the genome, although much of the data collected thus far argue against this interpretation. There is clearly more to learn here.
If, in fact, it is true that disabling the Rb and p53 pathways is a hallmark of cancer, then the most efficacious treatment would be to restore their functions. The inability to specifically target genes to tumor cells and to properly regulate their expression makes "gene therapy" impractical. Novel therapeutics will likely need to target ancillary pathways. Can we take advantage of weaknesses in tumors lacking Rb and/or p53 to selectively kill them? One rationale is based on the concept of "synthetic lethality" in yeast, in which disruption of one gene–in this case, Rb and/or p53–might sensitize cells to disruption of another pathway while sparing cells that retain either one of the two functions. Cyclin A-cdk2 activity is required to terminate E2F function in S phase, and blocking this function triggers apoptosis (112, 113) . One idea, then, is that cells that lack Rb and p53 checkpoints might prove more sensitive than normal cells to cdk inhibitors (114) , which are now being widely developed. The recent realization that cells lacking a p53-inducible nuclear subunit of ribonucleotide reductase may rely on a cytoplasmic form of this enzyme to resist drug-induced genotoxic damage (115) may provide another opportunity for targeted therapy. Others have speculated that if specific inhibitors of the cytoplasmic form of ribonucleotide reductase could be developed, these might selectively sensitize cells with mutant p53 to DNA-damaging chemotherapeutic agents (116) . Yet another approach would be to activate the apoptotic machinery downstream of the sensory signals that normally lead to p53-dependent activation, e.g., by activating death-inducing receptors that couple to caspases (117) . An article of faith is that a better understanding of cancer cells will lead to new drug targets and novel therapeutic approaches–that good science will lead to good medicine. Here, again, I quote from Thomas:
"It is much more difficult to be convincing about ignorance concerning disease mechanisms than it is to make claims for full comprehension, especially when the comprehension leads, logically or not, to some sort of action. When it comes to serious illness, the public tends, understandably, to be more skeptical about the skeptics, more willing to believe the true believers. It is medicine’s oldest dilemma, not to be settled by candor ... What it needs is a lot of time and patience, waiting for the science to come in, as it has in the past, with the solid facts" (118) .
We should be optimistic that the learning curve is accelerating.
ACKNOWLEDGMENTS
I thank the Pezcoller Foundation and the AACR for honoring me with this prize. All scientists build their careers on the shoulders of those who taught them and the many who have worked with them, both as colleagues and trainees. I thank my mentors, Ross Basch, Jonathan Uhr, Burton Goldberg, and George Todaro, for their guidance early in my career; my many colleagues at the NIH and St. Jude Children’s Research Hospital over a period of >25 years; and in particular, the many postdoctoral fellows who have shared in discovery along the way. Finally, I thank my wife, Martine Roussel, who, apart from everything else in our lives together, has worked closely with me in the laboratory for the last 17 years–as a Leo, she deserves a lion’s share.
FOOTNOTES
1 To whom requests for reprints should be
addressed, at Department of Tumor Cell Biology, St. Jude Children’s
Research Hospital, 332 North Lauderdale, Memphis, Tennessee 38105.
Phone: (901) 495-3505; Fax: (901) 495-2381; E-mail: sherr{at}stjude.org 
2 The abbreviations used are: cdk,
cyclin-dependent kinase; Rb, retinoblastoma protein; ARF, alternative
reading frame; MEF, mouse embryo fibroblast.
Received 4/18/00. Accepted 5/ 8/00.
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 S. B. Glickstein, J. A. Monaghan, H. B. Koeller, T. K. Jones, and M. E. Ross Cyclin D2 Is Critical for Intermediate Progenitor Cell Proliferation in the Embryonic Cortex J. Neurosci., July 29, 2009; 29(30): 9614 - 9624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. KOSACKA, P. PIESIAK, I. POREBSKA, A. KORZENIEWSKA, T. DYLA, and R. JANKOWSKA Cyclin A and Cyclin E Expression in Resected Non-small Cell Lung Cancer Stage I-IIIA In Vivo, July 1, 2009; 23(4): 519 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Borzacchiello, S. Mogavero, G. De Vita, S. Roperto, L.D. Salda, and F. Roperto Activated Platelet-Derived Growth Factor {beta} Receptor Expression, PI3K-AKT Pathway Molecular Analysis, and Transforming Signals in Equine Sarcoids Vet. Pathol., July 1, 2009; 46(4): 589 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Eguchi, H. Itadani, T. Shimomura, N. Kawanishi, H. Hirai, and H. Kotani Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines Mol. Cancer Ther., June 1, 2009; 8(6): 1460 - 1472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Peng, Q. Hu, X. Liu, L. Wang, Q. Chang, J. Li, J. Tang, N. Wang, and Y. Wang Duchesnea Phenolic Fraction Inhibits In Vitro and In Vivo Growth of Cervical Cancer Through Induction of Apoptosis and Cell Cycle Arrest Experimental Biology and Medicine, January 1, 2009; 234(1): 74 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. Nguyen, I. Aronchik, G. A. Brar, D. H. H. Nguyen, L. F. Bjeldanes, and G. L. Firestone The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing PNAS, December 16, 2008; 105(50): 19750 - 19755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Koutsami, G. Velimezi, A. Kotsinas, K. Evangelou, A. G Papavassiliou, C. Kittas, and V. G. Gorgoulis Is exclusive Skp2 targeting always beneficial in cancer therapy? Blood, December 1, 2008; 112(12): 4777 - 4779. [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Larrea, J. Liang, T. Da Silva, F. Hong, S. H. Shao, K. Han, D. Dumont, and J. M. Slingerland Phosphorylation of p27Kip1 Regulates Assembly and Activation of Cyclin D1-Cdk4 Mol. Cell. Biol., October 15, 2008; 28(20): 6462 - 6472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Libertini, I. Iacuzzo, G. Perruolo, S. Scala, C. Ierano, R. Franco, G. Hallden, and G. Portella Bevacizumab Increases Viral Distribution in Human Anaplastic Thyroid Carcinoma Xenografts and Enhances the Effects of E1A-Defective Adenovirus dl922-947 Clin. Cancer Res., October 15, 2008; 14(20): 6505 - 6514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kianianmomeni, G. Nematollahi, and A. Hallmann A Gender-Specific Retinoblastoma-Related Protein in Volvox carteri Implies a Role for the Retinoblastoma Protein Family in Sexual Development PLANT CELL, September 1, 2008; 20(9): 2399 - 2419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. S. Brooks, E. S. Helton, S. Banerjee, M. Venable, L. Johnson, T. R. Schoeb, R. A. Kesterson, and D. F. Crawford G2E3 Is a Dual Function Ubiquitin Ligase Required for Early Embryonic Development J. Biol. Chem., August 8, 2008; 283(32): 22304 - 22315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Montanaro, D. Trere, and M. Derenzini Nucleolus, Ribosomes, and Cancer Am. J. Pathol., August 1, 2008; 173(2): 301 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Freedberg, S. H. Rigas, J. Russak, W. Gai, M. Kaplow, I. Osman, F. Turner, J. A. Randerson-Moor, A. Houghton, K. Busam, et al. Frequent p16-Independent Inactivation of p14ARF in Human Melanoma J Natl Cancer Inst, June 4, 2008; 100(11): 784 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Derenzini, G. Donati, G. Mazzini, L. Montanaro, M. Vici, C. Ceccarelli, D. Santini, M. Taffurelli, and D. Trere Loss of Retinoblastoma Tumor Suppressor Protein Makes Human Breast Cancer Cells More Sensitive to Antimetabolite Exposure Clin. Cancer Res., April 1, 2008; 14(7): 2199 - 2209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.S. Han, J.H. No, Y.T. Jeon, J.W. Kim, N.H. Park, Y.S. Song, S.B. Kang, and H.P. Lee Association of cyclin D1 G870A polymorphism with uterine leiomyoma in women whose body mass index values are above 25 kg/m2 Hum. Reprod., March 1, 2008; 23(3): 525 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Weber, M. K. Corbett, L. M. L. Chow, M. B. Valentine, S. J. Baker, and J. Zuo Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells PNAS, January 15, 2008; 105(2): 781 - 785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Bentley, G. Normand, J. Hoyt, and R. W. King Distinct Sequence Elements of Cyclin B1 Promote Localization to Chromatin, Centrosomes, and Kinetochores during Mitosis Mol. Biol. Cell, December 1, 2007; 18(12): 4847 - 4858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Das, J. James, S. Bhattacharya, A. N. Imbalzano, M. L. Antony, G. Hegde, X. Zhao, K. Mallya, F. Ahmad, E. Knudsen, et al. SWI/SNF Chromatin Remodeling ATPase Brm Regulates the Differentiation of Early Retinal Stem Cells/Progenitors by Influencing Brn3b Expression and Notch Signaling J. Biol. Chem., November 30, 2007; 282(48): 35187 - 35201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Glickstein, H. Moore, B. Slowinska, J. Racchumi, M. Suh, N. Chuhma, and M. E. Ross Selective cortical interneuron and GABA deficits in cyclin D2-null mice Development, November 15, 2007; 134(22): 4083 - 4093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Koslowski, U. Sahin, R. Mitnacht-Kraus, G. Seitz, C. Huber, and O. Tureci A Placenta-Specific Gene Ectopically Activated in Many Human Cancers Is Essentially Involved in Malignant Cell Processes Cancer Res., October 1, 2007; 67(19): 9528 - 9534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lee, W. C. Park, H. W. Yim, M. A. Lee, G. Park, and K. Y. Lee Expression of c-erbB2, cyclin D1 and Estrogen Receptor and their Clinical Implications in the Invasive Ductal Carcinoma of the Breast Jpn. J. Clin. Oncol., September 1, 2007; 37(9): 708 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Alonso, M. Cascallo, C. Gomez-Manzano, H. Jiang, B. N. Bekele, A. Perez-Gimenez, F. F. Lang, Y. Piao, R. Alemany, and J. Fueyo ICOVIR-5 Shows E2F1 Addiction and Potent Antiglioma Effect In vivo Cancer Res., September 1, 2007; 67(17): 8255 - 8263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Lehmann and M. J. McCabe Jr Arsenite Slows S Phase Progression via Inhibition of cdc25A Dual Specificity Phosphatase Gene Transcription Toxicol. Sci., September 1, 2007; 99(1): 70 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-W. Lee, H. J. Kim, Y. S. Lee, H.-J. Park, J.-W. Choi, J. Ha, and K.-T. Lee Acteoside inhibits human promyelocytic HL-60 leukemia cell proliferation via inducing cell cycle arrest at G0/G1 phase and differentiation into monocyte Carcinogenesis, September 1, 2007; 28(9): 1928 - 1936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Fosmire, R. Thomas, C. M. Jubala, J. W. Wojcieszyn, V. E. O. Valli, D. M. Getzy, T. L. Smith, L. A. Gardner, M. G. Ritt, J. S. Bell, et al. Inactivation of the p16 Cyclin-Dependent Kinase Inhibitor in High-Grade Canine Non-Hodgkin's T-Cell Lymphoma Vet. Pathol., July 1, 2007; 44(4): 467 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ruas, F. Gregory, R. Jones, R. Poolman, M. Starborg, J. Rowe, S. Brookes, and G. Peters CDK4 and CDK6 Delay Senescence by Kinase-Dependent and p16INK4a-Independent Mechanisms Mol. Cell. Biol., June 15, 2007; 27(12): 4273 - 4282. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Matsumoto, S. Yu, Y. Jia, M. R. Ahmed, N. Viswakarma, J. Sarkar, P. V. Kashireddy, M. Sambasiva Rao, W. Karpus, F. J. Gonzalez, et al. Critical Role for Transcription Coactivator Peroxisome Proliferator-activated Receptor (PPAR)-binding Protein/TRAP220 in Liver Regeneration and PPAR{alpha} Ligand-induced Liver Tumor Development J. Biol. Chem., June 8, 2007; 282(23): 17053 - 17060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Barnett, D. Tomic, R. K. Gupta, K. P. Miller, S. Meachum, T. Paulose, and J. A. Flaws The Aryl Hydrocarbon Receptor Affects Mouse Ovarian Follicle Growth via Mechanisms Involving Estradiol Regulation and Responsiveness Biol Reprod, June 1, 2007; 76(6): 1062 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Shu, S. Lv, Y. Qin, X. Ma, X. Wang, X. Peng, Y. Luo, B.-e Xu, X. Sun, and J. Wu Functional characterization of human PFTK1 as a cyclin-dependent kinase PNAS, May 29, 2007; 104(22): 9248 - 9253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Perez de Castro, G. de Carcer, and M. Malumbres A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy Carcinogenesis, May 1, 2007; 28(5): 899 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ray, Y. Terao, P. G. Fuhrken, Z.-Q. Ma, F. J. DeMayo, K. Christov, N. A. Heerema, R. Franks, S. Y. Tsai, E. T. Papoutsakis, et al. Deregulated CDC25A Expression Promotes Mammary Tumorigenesis with Genomic Instability Cancer Res., February 1, 2007; 67(3): 984 - 991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Jiang, P. J. Mikochik, J. H. Ra, H. Lei, K. T. Flaherty, J. D. Winkler, and F. R. Spitz HIV Protease Inhibitor Nelfinavir Inhibits Growth of Human Melanoma Cells by Induction of Cell Cycle Arrest Cancer Res., February 1, 2007; 67(3): 1221 - 1227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Upton and S. H. Speck Evidence for CDK-Dependent and CDK-Independent Functions of the Murine Gammaherpesvirus 68 v-Cyclin J. Virol., December 15, 2006; 80(24): 11946 - 11959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Zhou, H. Kitaura, S. L. Teitelbaum, G. Krystal, F. P. Ross, and S. Takeshita SHIP1 Negatively Regulates Proliferation of Osteoclast Precursors via Akt-Dependent Alterations in D-Type Cyclins and p27 J. Immunol., December 15, 2006; 177(12): 8777 - 8784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yang, S. Wu, X. Su, and W. S. May JAZ mediates G1 cell-cycle arrest and apoptosis by positively regulating p53 transcriptional activity Blood, December 15, 2006; 108(13): 4136 - 4145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Mukhopadhyay, E. A. Sausville, J. H. Doroshow, and K. K. Roy Molecular Mechanism of Adaphostin-mediated G1 Arrest in Prostate Cancer (PC-3) Cells: SIGNALING EVENTS MEDIATED BY HEPATOCYTE GROWTH FACTOR RECEPTOR, c-Met, AND p38 MAPK PATHWAYS J. Biol. Chem., December 8, 2006; 281(49): 37330 - 37344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Y. Locker, S. Hamilton, J. Harris, J. M. Jessup, N. Kemeny, J. S. Macdonald, M. R. Somerfield, D. F. Hayes, and R. C. Bast Jr ASCO 2006 Update of Recommendations for the Use of Tumor Markers in Gastrointestinal Cancer J. Clin. Oncol., November 20, 2006; 24(33): 5313 - 5327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P Singh and R. Agarwal Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr. Relat. Cancer, September 1, 2006; 13(3): 751 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Chung, M. C. Ostrowski, T. Romigh, T. Minaguchi, K. A. Waite, and C. Eng The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation Hum. Mol. Genet., September 1, 2006; 15(17): 2553 - 2559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Wang, J. Tsukada, T. Higashi, T. Mizobe, A. Matsuura, F. Mouri, N. Sawamukai, C. Ra, and Y. Tanaka Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP600125. Genes Cells, September 1, 2006; 11(9): 983 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Garcia-Morales, E. Hernando, E. Carrasco-Garcia, M. P. Menendez-Gutierrez, M. Saceda, and I. Martinez-Lacaci Cyclin D3 is down-regulated by rapamycin in HER-2-overexpressing breast cancer cells. Mol. Cancer Ther., September 1, 2006; 5(9): 2172 - 2181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Huang, A. Wallqvist, and D. G. Covell Targeting changes in cancer: assessing pathway stability by comparing pathway gene expression coherence levels in tumor and normal tissues. Mol. Cancer Ther., September 1, 2006; 5(9): 2417 - 2427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. F. Dai, Y. Zhang, Y. Kang, Q. Wang, H. Y. Gaisano, K.-H. Braunewell, C. B. Chan, and M. B. Wheeler The Neuronal Ca2+ Sensor Protein Visinin-like Protein-1 Is Expressed in Pancreatic Islets and Regulates Insulin Secretion J. Biol. Chem., August 4, 2006; 281(31): 21942 - 21953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Croft and M. F. Olson The Rho GTPase Effector ROCK Regulates Cyclin A, Cyclin D1, and p27Kip1 Levels by Distinct Mechanisms Mol. Cell. Biol., June 15, 2006; 26(12): 4612 - 4627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Schnepp, Y.-X. Chen, H. Wang, T. Cash, A. Silva, J. A. Diehl, E. Brown, and X. Hua Mutation of Tumor Suppressor Gene Men1 Acutely Enhances Proliferation of Pancreatic Islet Cells Cancer Res., June 1, 2006; 66(11): 5707 - 5715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Shakhova, C. Leung, E. van Montfort, A. Berns, and S. Marino Lack of Rb and p53 Delays Cerebellar Development and Predisposes to Large Cell Anaplastic Medulloblastoma through Amplification of N-Myc and Ptch2. Cancer Res., May 15, 2006; 66(10): 5190 - 5200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Spaziani, A. Alisi, D. Sanna, and C. Balsano Role of p38 MAPK and RNA-dependent Protein Kinase (PKR) in Hepatitis C Virus Core-dependent Nuclear Delocalization of Cyclin B1 J. Biol. Chem., April 21, 2006; 281(16): 10983 - 10989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Oh, A. Razfar, I. Delgado, R. A. Reed, A. Malkina, B. Boctor, and D. J. Slamon 3p21.3 Tumor Suppressor Gene H37/Luca15/RBM5 Inhibits Growth of Human Lung Cancer Cells through Cell Cycle Arrest and Apoptosis. Cancer Res., April 1, 2006; 66(7): 3419 - 3427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Worsham, K. M. Chen, N. Tiwari, G. Pals, J. P. Schouten, S. Sethi, and M. S. Benninger Fine-mapping loss of gene architecture at the CDKN2B (p15INK4b), CDKN2A (p14ARF, p16INK4a), and MTAP genes in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg, April 1, 2006; 132(4): 409 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Ouyang, J. Li, Q. Ma, and C. Huang Essential roles of PI-3K/Akt/IKK{beta}/NF{kappa}B pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells Carcinogenesis, April 1, 2006; 27(4): 864 - 873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tzankov, A. Gschwendtner, F. Augustin, M. Fiegl, E. C. Obermann, S. Dirnhofer, and P. Went Diffuse large B-cell lymphoma with overexpression of cyclin e substantiates poor standard treatment response and inferior outcome. Clin. Cancer Res., April 1, 2006; 12(7): 2125 - 2132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Potemski, E. Pluciennik, A. K. Bednarek, R. Kusinska, D. Jesionek-Kupnicka, G. Pasz-Walczak, C. Watala, and R. Kordek Cyclin E Expression in Operable Breast Cancer Quantified Using Real-Time RT-PCR: A Comparative Study with Immunostaining Jpn. J. Clin. Oncol., March 1, 2006; 36(3): 142 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.J. Weroha, S. A. Li, O. Tawfik, and J. J. Li Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats Carcinogenesis, March 1, 2006; 27(3): 491 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Woodmansee, J. M. Kerr, E. A. Tucker, J. R. Mitchell, D. J. Haakinson, D. F. Gordon, E. C. Ridgway, and W. M. Wood The Proliferative Status of Thyrotropes Is Dependent on Modulation of Specific Cell Cycle Regulators by Thyroid Hormone Endocrinology, January 1, 2006; 147(1): 272 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cannon, E. Cesarman, and C. Boshoff KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2 Blood, January 1, 2006; 107(1): 277 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Schwartz and M. A. Shah Targeting the Cell Cycle: A New Approach to Cancer Therapy J. Clin. Oncol., December 20, 2005; 23(36): 9408 - 9421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. K.D.L. Reddy, R. V. Mettus, S. G. Rane, X. Grana, J. Litvin, and E. P. Reddy Cyclin-Dependent Kinase 4 Expression Is Essential for Neu-Induced Breast Tumorigenesis Cancer Res., November 15, 2005; 65(22): 10174 - 10178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nimmo, A. Antebi, and A. Woollard mab-2 encodes RNT-1, a C. elegans Runx homologue essential for controlling cell proliferation in a stem cell-like developmental lineage Development, November 15, 2005; 132(22): 5043 - 5054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Yang, L. Bancroft, J. Liang, M. Zhuang, and L. H. Augenlicht p27kip1 in Intestinal Tumorigenesis and Chemoprevention in the Mouse Cancer Res., October 15, 2005; 65(20): 9363 - 9368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Belanger, P. Beaulieu, C. Moreau, D. Labuda, T. J. Hudson, and D. Sinnett Functional promoter SNPs in cell cycle checkpoint genes Hum. Mol. Genet., September 15, 2005; 14(18): 2641 - 2648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Putnam, V. Pennaneach, and R. D. Kolodner Saccharomyces cerevisiae as a Model System To Define the Chromosomal Instability Phenotype Mol. Cell. Biol., August 15, 2005; 25(16): 7226 - 7238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Moser, J. W. Upton, R. D. Allen III, C. B. Wilson, and S. H. Speck Role of B-Cell Proliferation in the Establishment of Gammaherpesvirus Latency J. Virol., August 1, 2005; 79(15): 9480 - 9491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Yuste, J. C. Montero, A. Esparis-Ogando, and A. Pandiella Activation of ErbB2 by Overexpression or by Transmembrane Neuregulin Results in Differential Signaling and Sensitivity to Herceptin Cancer Res., August 1, 2005; 65(15): 6801 - 6810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Fraser, P. M. Watson, M. M. Fraig, J. R. Kelley, P. S. Nelson, A. M. Boylan, D. J. Cole, and D. K. Watson CaSm-Mediated Cellular Transformation Is Associated with Altered Gene Expression and Messenger RNA Stability Cancer Res., July 15, 2005; 65(14): 6228 - 6236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. I. Raynaud, S. R. Whittaker, P. M. Fischer, S. McClue, M. I. Walton, S. E. Barrie, M. D. Garrett, P. Rogers, S. J. Clarke, L. R. Kelland, et al. In vitro and In vivo Pharmacokinetic-Pharmacodynamic Relationships for the Trisubstituted Aminopurine Cyclin-Dependent Kinase Inhibitors Olomoucine, Bohemine and CYC202 Clin. Cancer Res., July 1, 2005; 11(13): 4875 - 4887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. G. Rodriguez-Mora, M. M. LaHair, J. A. McCubrey, and R. A. Franklin Calcium/Calmodulin-Dependent Kinase I and Calcium/Calmodulin-Dependent Kinase Kinase Participate in the Control of Cell Cycle Progression in MCF-7 Human Breast Cancer Cells Cancer Res., June 15, 2005; 65(12): 5408 - 5416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bueso-Ramos, Y. Xu, T. J. McDonnell, S. Brisbay, S. Pierce, H. Kantarjian, G. Rosner, and G. Garcia-Manero Protein Expression of a Triad of Frequently Methylated Genes, p73, p57Kip2, and p15, Has Prognostic Value in Adult Acute Lymphocytic Leukemia Independently of Its Methylation Status J. Clin. Oncol., June 10, 2005; 23(17): 3932 - 3939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wessely Interference by interferons: Janus faces in vascular proliferative diseases Cardiovasc Res, June 1, 2005; 66(3): 433 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Kushner, M. A. Ciemerych, E. Sicinska, L. M. Wartschow, M. Teta, S. Y. Long, P. Sicinski, and M. F. White Cyclins D2 and D1 Are Essential for Postnatal Pancreatic {beta}-Cell Growth Mol. Cell. Biol., May 1, 2005; 25(9): 3752 - 3762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sotillo, O. Renner, P. Dubus, J. Ruiz-Cabello, J. Martin-Caballero, M. Barbacid, A. Carnero, and M. Malumbres Cooperation between Cdk4 and p27kip1 in Tumor Development: A Preclinical Model to Evaluate Cell Cycle Inhibitors with Therapeutic Activity Cancer Res., May 1, 2005; 65(9): 3846 - 3852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tickenbrock, J. Schwable, M. Wiedehage, B. Steffen, B. Sargin, C. Choudhary, C. Brandts, W. E. Berdel, C. Muller-Tidow, and H. Serve Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction Blood, May 1, 2005; 105(9): 3699 - 3706. [Abstract] [Full Text] [PDF]
|
|
|
|
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I. Perez de Castro, M. Benet, M. Jimenez, S. Alzabin, M. Malumbres, and A. Pellicer Mouse p10, an Alternative Spliced Form of p15INK4b, Inhibits Cell Cycle Progression and Malignant Transformation Cancer Res., April 15, 2005; 65(8): 3249 - 3256. [Abstract] [Full Text] [PDF]
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J. D. Wu, A. Odman, L. M. Higgins, K. Haugk, R. Vessella, D. L. Ludwig, and S. R. Plymate In vivo Effects of the Human Type I Insulin-Like Growth Factor Receptor Antibody A12 on Androgen-Dependent and Androgen-Independent Xenograft Human Prostate Tumors Clin. Cancer Res., April 15, 2005; 11(8): 3065 - 3074. [Abstract] [Full Text] [PDF]
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L. Hernandez, S. Bea, M. Pinyol, G. Ott, T. Katzenberger, A. Rosenwald, F. Bosch, A. Lopez-Guillermo, J. Delabie, D. Colomer, et al. CDK4 and MDM2 Gene Alterations Mainly Occur in Highly Proliferative and Aggressive Mantle Cell Lymphomas with Wild-type INK4a/ARF Locus Cancer Res., March 15, 2005; 65(6): 2199 - 2206. [Abstract] [Full Text] [PDF]
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A. Tanaka, M. Konno, S. Muto, N. Kambe, E. Morii, T. Nakahata, A. Itai, and H. Matsuda A novel NF-{kappa}B inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors Blood, March 15, 2005; 105(6): 2324 - 2331. [Abstract] [Full Text] [PDF]
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 X. Zhang, J. P. Gaspard, Y. Mizukami, J. Li, F. Graeme-Cook, and D. C. Chung Overexpression of Cyclin D1 in Pancreatic {beta}-Cells In Vivo Results in Islet Hyperplasia Without Hypoglycemia Diabetes, March 1, 2005; 54(3): 712 - 719. [Abstract] [Full Text] [PDF]
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 S.-W. Wang, S.-L. Pan, J.-H. Guh, H.-L. Chen, D.-M. Huang, Y.-L. Chang, S.-C. Kuo, F.-Y. Lee, and C.-M. Teng YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole] Exhibits a Novel Antiproliferative Effect and Arrests the Cell Cycle in G0-G1 in Human Hepatocellular Carcinoma Cells J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 917 - 925. [Abstract] [Full Text] [PDF]
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G. Normand, P. G. Hemmati, B. Verdoodt, C. von Haefen, J. Wendt, D. Guner, E. May, B. Dorken, and P. T. Daniel p14ARF Induces G2 Cell Cycle Arrest in p53- and p21-deficient Cells by Down-regulating p34cdc2 Kinase Activity J. Biol. Chem., February 25, 2005; 280(8): 7118 - 7130. [Abstract] [Full Text] [PDF]
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A. Garcia-Espana, E. Salazar, T.-T. Sun, X.-R. Wu, and A. Pellicer Differential Expression of Cell Cycle Regulators in Phenotypic Variants of Transgenically Induced Bladder Tumors: Implications for Tumor Behavior Cancer Res., February 15, 2005; 65(4): 1150 - 1157. [Abstract] [Full Text] [PDF]
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Z. Yu, J. Lin, Y. Xiao, J. Han, X. Zhang, H. Jia, Y. Tang, and Y. Li Induction of Cell-Cycle Arrest by all-trans Retinoic Acid in Mouse Embryonic Palatal Mesenchymal (MEPM) Cells Toxicol. Sci., February 1, 2005; 83(2): 349 - 354. [Abstract] [Full Text] [PDF]
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J. Brzezinski, A. Migodzinski, A. Toczek, J. Tazbir, and M. Dedecjus Patterns of Cyclin E, Retinoblastoma Protein, and p21Cip1/WAF1 Immunostaining in the Oncogenesis of Papillary Thyroid Carcinoma Clin. Cancer Res., February 1, 2005; 11(3): 1037 - 1043. [Abstract] [Full Text] [PDF]
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I. A. Stasinopoulos, Y. Mironchik, A. Raman, F. Wildes, P. Winnard Jr., and V. Raman HOXA5-Twist Interaction Alters p53 Homeostasis in Breast Cancer Cells J. Biol. Chem., January 21, 2005; 280(3): 2294 - 2299. [Abstract] [Full Text] [PDF]
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C. J. Nelsen, R. Kuriyama, B. Hirsch, V. C. Negron, W. L. Lingle, M. M. Goggin, M. W. Stanley, and J. H. Albrecht Short Term Cyclin D1 Overexpression Induces Centrosome Amplification, Mitotic Spindle Abnormalities, and Aneuploidy J. Biol. Chem., January 7, 2005; 280(1): 768 - 776. [Abstract] [Full Text] [PDF]
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 P. WORKMAN Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 499 - 515. [Abstract] [PDF]
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J. Vondracek, M. Machala, V. Bryja, K. Chramostova, P. Krcmar, C. Dietrich, A. Hampl, and A. Kozubik Aryl Hydrocarbon Receptor-Activating Polychlorinated Biphenyls and Their Hydroxylated Metabolites Induce Cell Proliferation in Contact-Inhibited Rat Liver Epithelial Cells Toxicol. Sci., January 1, 2005; 83(1): 53 - 63. [Abstract] [Full Text] [PDF]
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M. Fu, C. Wang, Z. Li, T. Sakamaki, and R. G. Pestell Minireview: Cyclin D1: Normal and Abnormal Functions Endocrinology, December 1, 2004; 145(12): 5439 - 5447. [Abstract] [Full Text] [PDF]
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A. H. Box and D. J. Demetrick Cell cycle kinase inhibitor expression and hypoxia-induced cell cycle arrest in human cancer cell lines Carcinogenesis, December 1, 2004; 25(12): 2325 - 2335. [Abstract] [Full Text] [PDF]
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M. Rosner and M. Hengstschlager Tuberin Binds p27 and Negatively Regulates Its Interaction with the SCF Component Skp2 J. Biol. Chem., November 19, 2004; 279(47): 48707 - 48715. [Abstract] [Full Text] [PDF]
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W. Wang, J. Cassidy, V. O'Brien, K. M. Ryan, and E. Collie-Duguid Mechanistic and Predictive Profiling of 5-Fluorouracil Resistance in Human Cancer Cells Cancer Res., November 15, 2004; 64(22): 8167 - 8176. [Abstract] [Full Text] [PDF]
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M. Noseda, L. Chang, G. McLean, J. E. Grim, B. E. Clurman, L. L. Smith, and A. Karsan Notch Activation Induces Endothelial Cell Cycle Arrest and Participates in Contact Inhibition: Role of p21Cip1 Repression Mol. Cell. Biol., October 15, 2004; 24(20): 8813 - 8822. [Abstract] [Full Text] [PDF]
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M. M. Al-Aynati, N. Radulovich, J. Ho, and M.-S. Tsao Overexpression of G1-S Cyclins and Cyclin-Dependent Kinases during Multistage Human Pancreatic Duct Cell Carcinogenesis Clin. Cancer Res., October 1, 2004; 10(19): 6598 - 6605. [Abstract] [Full Text] [PDF]
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J. Wang, T. Wiltshire, Y. Wang, C. Mikell, J. Burks, C. Cunningham, E. S. Van Laar, S. J. Waters, E. Reed, and W. Wang ATM-dependent CHK2 Activation Induced by Anticancer Agent, Irofulven J. Biol. Chem., September 17, 2004; 279(38): 39584 - 39592. [Abstract] [Full Text] [PDF]
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C. C. Leow, M. S. Romero, S. Ross, P. Polakis, and W.-Q. Gao Hath1, Down-Regulated in Colon Adenocarcinomas, Inhibits Proliferation and Tumorigenesis of Colon Cancer Cells Cancer Res., September 1, 2004; 64(17): 6050 - 6057. [Abstract] [Full Text] [PDF]
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D. Tomic, K. P. Miller, H. A. Kenny, T. K. Woodruff, P. Hoyer, and J. A. Flaws Ovarian Follicle Development Requires Smad3 Mol. Endocrinol., September 1, 2004; 18(9): 2224 - 2240. [Abstract] [Full Text] [PDF]
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