Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell cycle progression is monitored by surveillance mechanisms, or cell cycle checkpoints, that ensure that initiation of a later event is coupled with the completion of an early cell cycle event. Deregulated proliferation is a characteristic feature of tumor cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cancer formation and progression. Key among these are p53, the retinoblastoma protein (pRb) and its related proteins, p107 and pRb2/p130, and cdk inhibitors (p15, p16, p18, p19, p21, p27), all of which act to keep the cell cycle from progressing until all repairs to damaged DNA have been completed. The pRb (pRb/p16(INK4a)/cyclin D1) and p53 (p14(ARF)/mdm2/p53) pathways are the two main cell-cycle control pathways frequently targeted in tumorigenesis, and the alterations occurring in each pathway depend on the tumor type. Virtually all human tumors deregulate either the pRb or p53 pathway, and oftentimes both pathways simultaneously. This review focuses on the genetic and epigenetic alterations affecting the components of mechanisms regulating the progression of the cell cycle and leading to cancer formation and progression.
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PMID:Modulation of cell cycle components by epigenetic and genetic events. 1621 85

Because each change in the evolution of a cancer is predicated on the effects of previous events, a full understanding of selective changes and their effect on tumor progression can only be understood in the context of appropriate initiating events. Here, we define the effect of pRb function inactivation in prostate epithelium on both the initiation of prostate cancer and the establishment of selective pressures that lead to diminished Pten function and tumor evolution. Using genetically engineered mice, we show that inactivation of the pRb family proteins (Rb/p107/p130) induces epithelial proliferation and apoptosis and is sufficient to produce prostatic intraepithelial neoplasia (PIN) lesions. Over time, adenocarcinomas develop in all mice with no evidence of neuroendocrine tumors. Apoptosis is dependent on Pten function and not p53, unlike other epithelial cell types tested previously. Consequently, Pten hemizygosity reduces apoptosis by 50%, accelerating progression to adenocarcinomas with heterogeneous composition. Heterogeneity is associated with concurrent Pten haploinsufficiency and focal selective progression to complete Pten loss, which yields distinct tumor properties. Given that this analysis models the apparent timing of highly penetrant events in human prostate cancer, observed effects may recapitulate the natural evolution of prostate cancer development.
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PMID:Heterogeneous tumor evolution initiated by loss of pRb function in a preclinical prostate cancer model. 1628 12

We hypothesized that combined transgenic overexpression of hepatocyte growth factor (HGF) and placental lactogen in islets would lead to even greater increases in beta-cell mass and replication than either growth factor alone. This did not occur, suggesting that beta-cell replication is saturable or subject to molecular restraint. We therefore performed the first comprehensive G(1)/S cell cycle survey in islets, cataloguing the broad range of kinases, cyclins, and kinase inhibitors that control the G(1)/S transition in islets from normal, HGF, placental lactogen, and doubly transgenic mice. Many of the G(1)/S checkpoint regulators (E2Fs; pRb; p107; p130; cyclins D(1),(2),(3), A, and E; cdk-2; cdk-4; p15; p16; p18; p19; p21; p27; MDM2; p53; c-Myc; and Egr-1) are present in the murine islet. Most of these proteins were unaltered by overexpression of HGF or placental lactogen, either alone or in combination. In contrast, p21(cip) was uniquely, dramatically, and reproducibly upregulated in placental lactogen and HGF islets. p21(cip) was also present in, and upregulated in, proliferating human islets, localizing specifically in beta-cells and translocating to the nucleus on mitogenic stimulation. Homozygous p21(cip) loss releases islets from growth inhibition, markedly enhancing proliferation in response to HGF and placental lactogen.
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PMID:Evaluation of beta-cell replication in mice transgenic for hepatocyte growth factor and placental lactogen: comprehensive characterization of the G1/S regulatory proteins reveals unique involvement of p21cip. 1638 Apr 78

When treated with DNA-damaging chemotherapy agents, many cancer cells, in vivo and in vitro, undergo a terminal growth arrest and acquire a senescence-like phenotype. We investigated the molecular basis for this in breast cancer cells following a 2-hour treatment with 1 muM doxorubicin. Treated cells arrested in G1 and G2 phases of the cell cycle, with concomitant reductions in S-phase and G2-M regulatory genes. p53 and p21 protein levels increased within hours after treatment and were maintained for 5 to 6 days but were reduced 8 days posttreatment, though the cells remained growth arrested. Levels of p130 rose after drug treatment, and it was the primary RB family member recruited to the S-phase promoters cyclin A and PCNA and G2-M promoters cyclin B and cdc2, remaining present for the entire 8-day time period. In contrast, p107 protein and promoter occupancy levels declined sharply after drug treatment. RB was recruited to only the PCNA promoter. In MCF-7 cells with p130 knockdown, p107 compensated for p130 loss at all cell cycle gene promoters examined, allowing cells to retain the growth arrest phenotype. Cells with p130 and p107 knockdown similarly arrested, while cells with knockdown of all three family members failed to downregulate cyclin A and cyclin B. These results demonstrate a mechanistic role for p130 and compensatory roles for p107 and RB in the long-term senescence-like growth arrest response of breast cancer cells to DNA damage.
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PMID:Primary and compensatory roles for RB family members at cell cycle gene promoters that are deacetylated and downregulated in doxorubicin-induced senescence of breast cancer cells. 1653 96

p21(cip1), a regulatory molecule upstream of the G(1/0) checkpoint, is increased in beta-cells in response to mitogenic stimulation. Whereas p21(cip1) can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that p21(cip1) acts as an inhibitor in the pancreatic beta-cell. To determine the functional role of p21(cip1) in vivo, we studied p21-null mice. Surprisingly, islet mass, beta-cell replication rates, and function were normal in p21-null mice. We next attempted to drive beta-cell replication in p21-null mice by crossing them with rat insulin II promoter-murine PL-1 (islet-targeted placental lactogen transgenic) mice. Even with this added replicative stimulus of PL, p21-null islets showed no additional stimulation. A G(1/S) proteome scan demonstrated that p21(cip1) loss was not associated with compensatory increases in other cell cycle inhibitors (pRb, p107, p130, p16, p19, and p27), although mild increases in p57 were apparent. Surprisingly, p18, which had been anticipated to increase, was markedly decreased. In summary, isolated p21(cip1) loss, as for pRb, p53, p18, and p27 and other inhibitors, results in normal beta-cell development and function, either because it is not essential or because its function is subserved or complimented by another protein. These studies underscore marked inhibitory pressure and the complexity and plasticity of inhibitory pathways that restrain beta-cell replication.
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PMID:The cell cycle inhibitory protein p21cip is not essential for maintaining beta-cell cycle arrest or beta-cell function in vivo. 1713 Apr 70

The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), p18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G1-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.
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PMID:Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. 1730 68

In contrast with the low frequency of alterations found in the Rb gene, the pRb pathway is inactivated in the vast majority of human tumors. A similar situation takes place in mouse models of cancer, including two-stage skin tumorigenesis. This might be explained if the Rb functions are carried out, in its absence, by other proteins that are also controlled by the same upstream regulators and display similar effectors. The other Rb family members, p107 and or p130, are plausible candidates. The embryonic lethality of pRb-deficient animals, which precludes the analysis of the roles of Rb gene in mouse models, has been avoided using tissue-specific deletion of pRb. In epidermis, pRb deletion leads to altered proliferation and differentiation. However, these deficient mice do not develop spontaneous tumors, and chemical carcinogenesis experiments revealed that the absence of pRb renders fewer and smaller tumors than control animals, but showing increased malignant conversion to squamous cell carcinomas (SCC). Detailed biochemical analyses have indicated that, in the absence of pRb, multiple pathways, including the aberrant p53 activation mediated by E2F/p19(ARF), are activated leading to increased tumor apoptosis. As Rb loss in epidermis is functionally compensated by Rbl1 (p107), this might also suggest that p107 could behave as a tumor suppressor. We summarize here our findings in support of this hypothesis. The pRb-;p107-/- epidermis form spontaneous tumors, and the reduction of p107 levels restores the susceptibility of pRb-mice to chemical skin carcinogenesis experiments. Moreover, Rb-deficient keratinocytes are highly susceptible to Ha-ras-induced transformation, and this susceptibility is enhanced by p107 loss. Further functional studies have indicated that the loss of p107 in the absence of pRb produces the reduction of p53-dependent proapoptotic signals through the modulation of p63 and p73 isoforms. In addition, expression profiling analysis has revealed multiple oncogenic alterations that can contribute to tumor susceptibility in epidermis in the absence of pRb and p107.
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PMID:The Rb family connects with the Tp53 family in skin carcinogenesis. 1748 38

Centromeric Protein-F (Cenp-F) family members have been identified in organisms from yeast to human. Cenp-F proteins are a component of kinetochores during mitosis, bind to the Rb family of tumor suppressors, and have regulatory effects on the cell cycle and differentiation; however, their role in these processes has not been resolved. Here, we provide evidence that the role of murine Cenp-F (mCenp-F, also known as LEK1) remains largely conserved and that the domains within the C-terminus collectively function to regulate the G2/M cell cycle checkpoint. Overexpression of the C-terminal domain of mCenp-F decreases DNA synthesis. Analyses of deletion mutants of mCenp-F reveal that the complete C-terminal domain is required to delay cell cycle progression at G2/M. Signal transduction pathway profiling experiments indicate that the mCenp-F-mediated cell cycle delay does not involve transcriptional activity of key cell cycle regulators such as Rb, E2F, p53, or Myc. However, endogenous mCenp-F colocalizes with pRb and p107, which demonstrates in vivo protein-protein interaction during cell division. These observations suggest that the domains of the C-terminus of mCenp-F have a conserved function in control of mitotic progression through protein-protein interaction with pocket proteins, thus providing a direct connection between cell cycle regulation and mitotic progression.
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PMID:Conserved C-terminal domains of mCenp-F (LEK1) regulate subcellular localization and mitotic checkpoint delay. 1749 89

The activity of Rb (retinoblastoma protein) is regulated by phosphorylation and acetylation events. Active Rb is hypophosphorylated and acetylated on multiple residues. Inactivation of Rb involves concerted hyper-phosphorylation by cyclin-CDK (cyclin-dependent kinase) complexes combined with deacetylation of appropriate lysine residues within Rb. In the present study, using in vivo co-immunoprecipitation experiments, we identified mammalian SIRT1 (sirtuin 1) as a binding partner for Rb and its family members p107 and p130. Formation of Rb-SIRT1 complexes required the pocket domain of Rb. p300 catalysed the acetylation of Rb, and SIRT1 was a potent deacetylase for Rb. The ability of SIRT1 to catalyse the deacetylation of Rb was dependent on NAD and was inhibited by the SIRT1 inhibitor nicotinamide. Deacetylated lysine residues within Rb formed a domain similar to the SIRT1-targeted domain of the p53 tumour suppressor protein. Cultures of arrested cells, via contact inhibition or DNA damage, exhibited decreased Rb phosphorylation and increased Rb acetylation. Overexpression of SIRT1 in either confluent or etoposide-treated cells resulted in a significant reduction in Rb acetylation, which was restored with nicotinamide. Gene knockdown of SIRT1 by siRNA (short interfering RNA) produced an accumulation of acetylated Rb. This increase was augmented further when siRNA against SIRT1 was used in conjunction with nicotinamide. In conclusion, our results demonstrate that SIRT1 is an in vitro and in vivo deacetylase for the Rb tumour suppressor protein.
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PMID:Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. 1762 57

Rb/E2F regulates many genes that encode proteins required for the cell cycle. Using affymetrix microarrays we previously identified genes regulated by the Rb proteins p130 and p107, many of which are involved in the cell cycle. Several genes with unknown functions were also repressed by p130 and p107, of which some have recently been found to have various roles in mitosis, the spindle checkpoint and cytokinesis. This study focuses on the regulation of borealin/dasra/cdca8, which encodes a recently discovered member of the chromosomal passenger complex. It is recorded that borealin is a cell cycle regulator, down-regulated in response to p53/Rb-signaling, and up-regulated in many types of cancerous tissues.
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PMID:Borealin is repressed in response to p53/Rb signaling. 1771 30


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