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)

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

This study reports the results of mutation detection of tumour suppressor genes, p53 and RB2/p130 genes in Malaysian nasopharyngeal carcinoma (NPC) studied by PCR-CSGE analysis and direct DNA sequencing method. Frequent sites of mutation in both genes (exons 5-8 of p53 and exons 19-21 of RB2/p130) were examined. Thirty-six NPC blood samples and three NPC cell lines were investigated for the presence of mutations. No mutation of p53 and RB2/p130 genes was identified in any of the blood samples. Nonetheless, there was an identical G-->4 C nucleotide change at codon 280 of p53 gene in all the cell lines. A larger study that includes biopsy tissues should be carried out to provide a more in-depth look into the pathogenesis of NPC in Malaysia.
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PMID:Mutational analysis of p53 and RB2/p130 genes in Malaysian nasopharyngeal carcinoma samples: a preliminary report. 1769 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

Functional inactivation of the pRb-dependent pathway is a general feature of human cancer. However, only a reduced spectrum of tumors displays inactivation of the Rb gene. This can be attributed, at least partially, to the possible overlapping functions carried out by the related retinoblastoma family members p107 and p130. We observed that loss of pRb in epidermis, using the Cre/LoxP technology, results in proliferation and differentiation defects. These alterations are partially compensated by the elevation in the levels of p107. Moreover, epidermis lacking pRb and p107, but not pRb alone, develops spontaneous tumors, and double deficient primary keratinocytes are highly susceptible to Ha-ras-induced transformation. Two-stage chemical carcinogenesis experiments in mice lacking pRb in epidermis revealed a reduced susceptibility in papilloma formation and an increase in the malignant conversion. We have now explored whether the loss of one p107 allele, inducing a decrease in the levels of p107 up to normal levels could restore the susceptibility of pRb-deficient skin to two-stage protocol. We observed partial restoration in the incidence, number, and size of tumors. However, there is no increased malignancy despite sustained p53 activation. We also observed a partial reduction in the levels of proapoptotic proteins in benign papillomas. These data confirm our previous suggestions on the role of p107 as a tumor suppressor in epidermis in the absence of pRb.
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PMID:Susceptibility of pRb-deficient epidermis to chemical skin carcinogenesis is dependent on the p107 allele dosage. 1830 Feb 54

Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.
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PMID:Distinct roles for p107 and p130 in Rb-independent cellular senescence. 1841 57

Novel murine models of retinoblastoma based on Rb gene deletion in concert with inactivation of Rb family members have recently been developed. These new Rb knockout models of retinoblastoma provide excellent tools for pre-clinical studies and for the exploration of the genetics of tumorigenesis driven by RB inactivation. This review focuses on the developmental consequences of Rb deletion in the retina and the genetic interactions between Rb and the two other members of the pocket protein family, p107 (Rbl1) and p130 (Rbl2). There is increasing appreciation that homozygous RB mutations are insufficient for human retinoblastoma. Identifying and understanding secondary gene alterations that cooperate with RB inactivation in tumorigenesis may be facilitated by mouse models. Recent investigation of the p53 pathway in retinoblastoma, and evidence of spatial topology to early murine retinoblastoma are also discussed in this review.
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PMID:Insights from mouse models into human retinoblastoma. 1848 54

Certain human papillomaviruses (such as HPV-16 and HPV-18) are associated with specific anogenital cancers, most notably cervical cancer. These viruses encode two oncoproteins, E6 and E7, which are expressed in the HPV positive cancers. E7 functions in cellular transformation, at least in part, through inactivation of pRB, and the other pRB related "pocket proteins" p107 and p130. The major target of the E6 oncoprotein encoded by the genital tract, cancer-associated human papillomaviruses is the p53 tumor suppressor protein. E6 binding to p53 is mediated by a cellular protein, the E6-associated protein (E6AP). In the presence of E6, E6AP catalyses the ubiquitylation and proteolysis of p53. E6AP is an E3 ubiquitin protein ligase and is not normally involved in the regulation of p53 stability in the absence of E6. E6AP is the prototype for the HECT domain family of E3 ubiquitin protein ligases.
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PMID:Warts, cancer and ubiquitylation: lessons from the papillomaviruses. 1852 68

Mouse embryonic fibroblasts (MEFs) deficient for pocket proteins (i.e., pRB/p107-, pRB/p130-, or pRB/p107/p130-deficient MEFs) have lost proper G(1) control and are refractory to Ras(V12)-induced senescence. However, pocket protein-deficient MEFs expressing Ras(V12) were unable to exhibit anchorage-independent growth or to form tumors in nude mice. We show that depending on the level of pocket proteins, loss of adhesion induces G(1) and G(2) arrest, which could be alleviated by overexpression of the TBX2 oncogene. TBX2-induced transformation occurred only in the absence of pocket proteins and could be attributed to downregulation of the p53/p21(CIP1) pathway. Our results show that a balance between the pocket protein and p53 pathways determines the level of transformation of MEFs by regulating cyclin-dependent kinase activities. Since transformation of human fibroblasts also requires ablation of both pathways, our results imply that the mechanisms underlying transformation of human and mouse cells are not as different as previously claimed.
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PMID:Anchorage-independent growth of pocket protein-deficient murine fibroblasts requires bypass of G2 arrest and can be accomplished by expression of TBX2. 1893 68

In response to DNA damage, several signaling pathways that arrest the cell cycle in G(1) and G(2) are activated. The down-regulation of mitotic genes contributes to the stable maintenance of the G(2) arrest. The human LINC or DREAM complex, together with the B-MYB transcription factor, plays an essential role in the expression of G(2)-M genes. Here, we show that DNA damage results in the p53-dependent binding of p130 and E2F4 to LINC and the dissociation of B-MYB from LINC. We find that B-MYB fails to dissociate from LINC in p53 mutant cells, that this contributes to increased G(2)-M gene expression in response to DNA damage in these cells, and, importantly, that B-MYB is required for recovery from the G(2) DNA damage checkpoint in p53-negative cells. Reanalysis of microarray expression data sets revealed that high levels of B-MYB correlate with a p53 mutant status and an advanced tumor stage in primary human breast cancer. Taken together, these data suggest that B-MYB/LINC plays an important role in the DNA damage response downstream of p53.
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PMID:B-MYB is required for recovery from the DNA damage-induced G2 checkpoint in p53 mutant cells. 1938 8

Cellular levels of products from both oncogenes and tumor suppressor genes in normal cells need to be critically regulated to avoid malignant transformation. These products are often controlled by the ubiquitin proteasome pathway, the specific degradation mechanism in the cell. E3 ubiquitin ligases polyubiquitylate their specific substrates by collaborating with E1 and E2, and then the modified substrates are degraded in the proteasome. Mdm2 targets p53 and retinoblastoma protein, two major tumor suppressor gene products, for ubiquitin-dependent degradation. SCF(Skp2) targets other tumor suppressor gene products and CDK inhibitors such as p130, Tob1, p27(Kip1), p57(Kip2), and p21(Cip1). Therefore, both E3 ligases act like oncogene products. In contrast, degradation of several oncogene products, such as Cyclin E, Notch, c-Myc, c-Jun, and c-Myb, are mediated by SCF(Fbw7). Fbw7 is often deleted or mutated in human cancers and acts like a tumor suppressor. As well as growth factor receptors and signal transduction regulators, DNA repair-related proteins are also regulated via the ubiquitin-proteasome pathway mediated by their specific E3 ligases. The stabilization of oncogene products and enhanced degradation of tumor suppressor gene products or DNA repair proteins might be associated with carcinogenesis and malignant progression, due to defects or the abnormal expression of their E3 ligases.
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PMID:Ubiquitin-mediated control of oncogene and tumor suppressor gene products. 1945 46


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