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

The p19(ARF) tumor suppressor antagonizes Mdm2 to induce p53-dependent cell cycle arrest. Individual TKO (triple knock out) mice nullizygous for ARF, p53, and Mdm2 develop multiple tumors at a frequency greater than those observed in animals lacking both p53 and Mdm2 or p53 alone, demonstrating that p19(ARF) can act independently of the Mdm2-p53 axis in tumor surveillance. Reintroduction of ARF into TKO mouse embryo fibroblasts (MEFs), but not into those lacking both p53 and ARF, arrested the cell division cycle in the G1 phase. Inhibition of the retinoblastoma protein had no effect on the ability of ARF to arrest TKO MEFs. Thus, in the absence of Mdm2, p19(ARF) interacts with other targets to inhibit cell proliferation.
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PMID:p53-independent functions of the p19(ARF) tumor suppressor. 1099 91

At least three domains of simian virus 40 large T antigen (TAg) participate in cellular transformation. The LXCXE motif of TAg binds to all members of the retinoblastoma protein (pRB) family of tumor suppressors. The N-terminal 70 residues of TAg have significant homology to the J domain of Hsp40/DnaJ and cooperate with the LXCXE motif to inactivate the pRB family. A bipartite C-terminal domain of TAg binds to p53 and thereby disrupts the ability of p53 to act as a sequence-specific transcription factor. The contribution of these three domains of TAg to cellular transformation was evaluated in cells that contained inactivating mutations in the pRB and p53 pathways. Cells that stably expressed wild-type or selected mutant forms of TAg were generated in mouse embryo fibroblasts (MEFs) containing homozygous deletions in the RB, INK4a, and ARF loci. It was determined that the J domain, the LXCXE motif, and the p53-binding domain of TAg were required for full transformation of wild-type and RB(-/-) MEFs. In contrast, INK4a(-/-) MEFs that lacked expression of p16(INK4a) and p19(ARF) and ARF(-/-) MEFs that lacked p19(ARF) but expressed p16(INK4a) acquired anchorage-independent growth when expressing wild-type TAg or mutant derivatives that disrupted either the pRB-binding or p53-binding domain. The expression and function of the pRB family members were not overly disrupted in ARF(-/-) MEFs expressing LXCXE mutants of TAg. These results suggest that inactivating mutations of p19(ARF) can relieve the requirement for the LXCXE motif in TAg-mediated transformation and that TAg may have additional functions in transformation.
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PMID:Loss of p19(ARF) eliminates the requirement for the pRB-binding motif in simian virus 40 large T antigen-mediated transformation. 1100 58

The INK4a/ARF locus at chromosome 9p21 encodes two structurally and functionally distinct molecules with tumor-suppressive properties. p16INK4a controls cell cycle progression by inhibiting phosphorylation of the retinoblastoma protein (Rb), while ARF prevents MDM2-mediated degradation of p53. By using a panel of PCR-based methods, we have examined the status of the p16INK4a, ARF and p53 genes in 123 cases of non-Hodgkin's lymphoma (NHL) at diagnosis. Alterations of one or more of these genes were detected in seven of 36 (19%) cases with low- to intermediate-grade histology, and in 35 of 87 (40%) cases with aggressive histology. For the aggressive lymphomas, the Kaplan-Meier estimate of overall survival for cases with disruption of either p16INK4a or the ARF-p53 pathway was not different from cases with retention of both pathways (5 year survival 45% vs 35%; P= 0.85), suggesting that selective inactivation of one of the pathways does not significantly influence overall survival. By contrast, the 5-year survival was only 7% for cases with concurrent disruption of p16INK4a and the ARF-p53 pathway vs 38% for cases with retention of one or both pathways (P = 0.005). Similar results were obtained when the analysis was confined to diffuse large B cell lymphomas (P= 0.019). On stepwise multivariate regression analysis including factors from the international prognostic index, concurrent disruption of p16INK4a and the ARF-p53 pathway was an independent negative prognostic factor in NHL with aggressive histology (P = 0.006). Our results suggest that the compound status of the p16INK4a and ARF-p53 pathways is a major determinant of outcome in NHL.
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PMID:Concurrent disruption of p16INK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma. 1102 47

Senescence is now understood to be the final phenotypic state adopted by a cell in response to several distinct cell physiological processes, including proliferation, oncogene activation and oxygen free radical toxicity. The role of telomere maintenance in immortalization and the roles of p16(INK4A), p19(ARF), p53 and other genes in senescence are being further elucidated. Significant progress continues to be made in our understanding of cellular senescence and immortalization.
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PMID:Genes involved in senescence and immortalization. 1106 35

MDM2 is over-expressed in several human tumors. Its product is a negative-feedback regulator of p53, which interferes with the control of cell proliferation and apoptosis, interacting not only with p53 but also with retinoblastoma (Rb) and E2F. Moreover, mutations in the ARF-Ink4a locus may also allow MDM2 to override p53 functions. In this study, we have used a novel oligonucleotide anti-sense MDM2, with mixed-backbone structure and demonstrate that it causes inhibition of MDM2 expression, induction of both p53 and p21/WAF1 expression and a dose-dependent, growth-inhibitory effect in human GEO colon-cancer cells. We also show that anti-sense MDM2 has a co-operative growth-inhibitory effect with different classes of cytotoxic drugs acting by different mechanisms. Moreover, anti-sense MDM2 induces apoptosis and markedly enhances the apoptotic activity of different cytotoxic drugs. Finally, we show that anti-sense MDM2 has anti-tumor activity in vivo in nude mice bearing GEO xenografts and potentiates the anti-tumor effect of cytotoxic drugs. Indeed, despite the short treatment period, the combination of anti-sense MDM2 and cytotoxic drugs causes a marked delay in tumor growth and prolongation of mice survival, lasting several months after treatment cessation. The anti-tumor effect is associated with inhibition of MDM2 expression in tumor specimens of animals treated with anti-sense MDM2, alone or in combination with a cytotoxic drug. Our results provide the rationale for development of a novel mixed-backbone anti-sense MDM2 into a clinical setting in therapeutic combination strategies with conventional cytotoxic drugs.
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PMID:A novel MDM2 anti-sense oligonucleotide has anti-tumor activity and potentiates cytotoxic drugs acting by different mechanisms in human colon cancer. 1107 52

Human astrocytomas are characterized by a number of molecular changes affecting two critical tumor suppressor pathways: the pRB and the p53 pathways. Genetic alterations functionally eliminate pRB and p53 themselves or upstream and/or downstream molecules such as products of the Ink4a/ARF locus, p16Ink4a and p14ARF. As a result, malignant cells are defective in critical cell cycle and apoptosis regulatory elements contributing to unrelenting tumour growth and invasion. Current research aims to discover effective means of reconstituting p53 and pRB pathway components in an effort to attenuate the aggressive phenotype of astrocytoma.
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PMID:Alterations of the p53 and pRB pathways in human astrocytoma. 1121 Jan 73

Members of the p53 family of transcription factors have essential roles in tumor suppression and in development. MDM2 is an essential regulator of p53 that can inhibit the transcriptional activity of p53, shuttle p53 out of the nucleus, and target p53 for ubiquitination-mediated degradation. Little is known about the interaction and selectivity of different members of the p53 family (p53, p63, and p73) and the MDM2 family (MDM2 and MDMX). Here we show that the transcriptional activities of p53 and p73, but not that of p63, were inhibited by both MDM2 and MDMX. Consistent with these, we found that MDMX can physically interact with p53 and p73, but not with p63. Moreover, ectopically expressed MDM2 and MDMX could induce alterations in the subcellular localization of p73, but did not affect the subcellular localization of p53 and p63. Finally, we demonstrate that while ARF can interact with MDM2 and inhibit the regulation of p53 by MDM2, no interaction was found between ARF and MDMX. These data reveal that significant differences and selectivity exist between the regulation of different members of the p53 family by MDM2 and MDMX.
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PMID:MDM2 and MDMX can interact differently with ARF and members of the p53 family. 1122 36

The INK4a-ARF locus encodes two tumor suppressor proteins involved in cell-cycle regulation, p16INK4a and p14ARF, whose functions are inactivated in many human cancers. The aim of this study was to evaluate p14ARF and p16INK4a gene inactivation and its association with some clinocopathological parameters in colon cancer. The mutational and methylation status of the p14ARF and p16INK4a genes was analyzed in 60 primary colon carcinomas and 8 colon cancer cell lines. We have identified the first two reported mutations affecting exon 1beta of p14ARF in the HCT116 cell line and in one of the primary colon carcinomas. Both mutations occur within the N-terminal region of p14ARF, documented as important for nucleolar localization and interaction with Mdm2. Tumor-specific methylation of the p14ARF and p16INK4a genes was found in 33% and 32% of primary colon carcinomas, respectively. Methylation of the p14ARF was inversely correlated with p53 overexpression (p = 0.02). p14ARF and p16INK4a gene methylation was significantly more frequent in right-sided than in left-sided tumors (p = 0.02). Methylation of the p14ARF gene occurred more frequently in well-differentiated adenocarcinomas (p = 0.005), whereas the p16INK4a gene was more often methylated in poorly differentiated adenocarcinomas (p = 0.002). The present results underline the role of p14ARF and p16INK4a gene inactivation in the development of colon carcinoma. They suggest that the methylation profile of specific genes, in particular p14ARF and p16INK4a, might be related to biologically distinct subsets of colon carcinomas and possibly to different tumorigenic pathways.
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PMID:Methylation silencing and mutations of the p14ARF and p16INK4a genes in colon cancer. 1123 44

Cells isolated from individuals with Cockayne syndrome (CS) have a defect in transcription-coupled DNA repair, which rapidly corrects certain DNA lesions located on the transcribed strand of active genes. Despite this DNA repair defect, individuals with CS group A (CSA) or group B (CSB) do not exhibit an increased spontaneous or UV-induced cancer rate. In order to investigate the effect of CSB deficiency on spontaneous carcinogenesis, we crossed CSB(-/-) mice with cancer-prone mice lacking the p16(Ink4a)/p19(ARF) tumor suppressor locus. CSB(-/-) mice are sensitive to UV-induced skin cancer but show no increased rate of spontaneous cancer. CSB(-/-) Ink4a/ARF(-/-) mice developed 60% fewer tumors than Ink4a/ARF(-/-) animals and demonstrated a longer tumor-free latency time (260 versus 150 days). Moreover, CSB(-/-) Ink4a/ARF(-/-) mouse embryo fibroblasts (MEFs) exhibited a lower colony formation rate after low-density seeding, a lower rate of H-Ras-induced transformation, slower proliferation, and a lower mRNA synthesis rate than Ink4a/ARF(-/-) MEFs. CSB(-/-) Ink4a/ARF(-/-) MEFs were also more sensitive to UV-induced p53 induction and UV-induced apoptosis than were Ink4a/ARF(-/-) MEFs. In order to investigate whether the apparent antineoplastic effect of CSB gene disruption was caused by sensitization to genotoxin-induced (p53-mediated) apoptosis or by p53-independent sequelae, we also generated p53(-/-) and CSB(-/-) p53(-/-) MEFs. The CSB(-/-) p53(-/-) MEFs demonstrated lower colony formation efficiency, a lower proliferation rate, a lower mRNA synthesis rate, and a higher rate of UV-induced cell death than p53(-/-) MEFs. Collectively, these results indicate that the antineoplastic effect of CSB gene disruption is at least partially p53 independent; it may result from impaired transcription or from apoptosis secondary to environmental or endogenous DNA damage.
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PMID:Disruption of the Cockayne syndrome B gene impairs spontaneous tumorigenesis in cancer-predisposed Ink4a/ARF knockout mice. 1123 17

The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4a(Delta2/3) deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RAS(V12G), Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate with p53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising in INK4a(Delta2/3-/-) mice, and whether tumor-associated mutations emerge in the p16(INK4a)-RB pathway in such melanomas. Here, we report that p53 inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on the INK4a(Delta2/3) null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G(1)/S transition, including c-Myc, cyclin D1, cdc25a, and p21(CIP1). Consistent with the profile of c-Myc dysregulation, the reintroduction of p16(INK4a) profoundly reduced the growth of Tyr-RAS INK4a(Delta2/3-/-) tumor cells but had no effect on tumor cells derived from Tyr-RAS p53(-/-) melanomas. Together, these data validate a role for p53 inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.
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PMID:Dual inactivation of RB and p53 pathways in RAS-induced melanomas. 1123 48


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