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)

In order to clarify the role of p53, known as a tumor suppressor protein and also as a key molecule of apoptotic cell death, we have studied p53 expression in relation to localization, time course, cell type, and TUNEL reaction in a rat model of transectional spinal cord injury. Other apoptosis related molecules, p21, Bcl-2 and Bax, that are in the cascade of p53 pathway, were also examined. p53 was expressed in cells residing in the vicinity of transection as early as 30 min. For the next 2 days, the positive cells spread in distribution, increased in number, and thereafter decreased. p53 immunoreactivity was localized primarily to the nucleus but not to cytoplasm. Double-staining with glial cell markers revealed that p53 immunoreactivity was often co-localized in microglia, oligodendrocytes and astrocytes, but not in neurons. In view of the results of the double-staining of p53 and Bcl-2, Bax or TUNEL, a variety of apoptosis-related molecules are expressed with p53, all within the first three days of injury. Further, the process of apoptosis via the p53, pathway appears complex even in this simple model of CNS injury. Our study suggests that the manipulation of these apoptosis-related molecules may prove useful in modifying the cell and tissue damage in traumatic CNS injury.
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PMID:Implications of p53 protein expression in experimental spinal cord injury. 1070 75

The ARF tumor suppressor protein stabilizes p53 by antagonizing its negative regulator, Mdm2 (Hdm2 in humans). Both mouse p19(ARF) and human p14(ARF) bind to the central region of Mdm2 (residues 210 to 304), a segment that does not overlap with its N-terminal p53-binding domain, nuclear import or export signals, or C-terminal RING domain required for Mdm2 E3 ubiquitin ligase activity. The N-terminal 37 amino acids of mouse p19(ARF) are necessary and sufficient for binding to Mdm2, localization of Mdm2 to nucleoli, and p53-dependent cell cycle arrest. Although a nucleolar localization signal (NrLS) maps within a different segment (residues 82 to 101) of the human p14(ARF) protein, binding to Mdm2 and nucleolar import of ARF-Mdm2 complexes are both required for cell cycle arrest induced by either the mouse or human ARF proteins. Because many codons of mouse ARF mRNA are not recognized by the most abundant bacterial tRNAs, we synthesized ARF minigenes containing preferred bacterial codons. Using bacterially produced ARF polypeptides and chemically synthesized peptides conjugated to Sepharose, residues 1 to 14 and 26 to 37 of mouse p19(ARF) were found to interact independently and cooperatively with Mdm2, while residues 15 to 25 were dispensable for binding. Paradoxically, residues 26 to 37 of mouse p19(ARF) are also essential for ARF nucleolar localization in the absence of Mdm2. However, the mobilization of the p19(ARF)-Mdm2 complex into nucleoli also requires a cryptic NrLS within the Mdm2 C-terminal RING domain. The Mdm2 NrLS is unmasked upon ARF binding, and its deletion prevents import of the ARF-Mdm2 complex into nucleoli. Collectively, the results suggest that ARF binding to Mdm2 induces a conformational change that facilitates nucleolar import of the ARF-Mdm2 complex and p53-dependent cell cycle arrest. Hence, the ARF-Mdm2 interaction can be viewed as bidirectional, with each protein being capable of regulating the subnuclear localization of the other.
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PMID:Cooperative signals governing ARF-mdm2 interaction and nucleolar localization of the complex. 1071 75

Human papillomaviruses (HPVs) are common DNA viruses in humans. Recently, epithelial cancers associated with HPV infection have been used as models of virus-induced carcinogenesis. HPVs can be divided into two groups, mucosal and cutaneous. HPV-16 is the most frequent mucosal type associated with cervical cancer. Although the molecular mechanisms of carcinogenesis by HPV-16 have not been completely elucidated, it is apparent that HPV infection is the major risk factor in cervical carcinogenesis. Two viral early genes, E6 and E7, and an upstream regulatory region (URR) are preserved in cervical carcinoma cell lines as well as in clinical samples of cervical cancer, indicating that these regions are important in cancer development. E6 and E7 function as transforming genes. E6 protein binds to and promotes degradation of the tumor suppressor protein, p53, while E7 protein complexes and inactivates the Rb protein; together, they disrupt cell cycle regulation. E6 and E7 are transcribed from a promoter, P97. P97 is regulated by complex interactions between multiple, positive and negative, cellular factors and the viral E2 product. E2 disruption caused by the integration into the cellular genome may induce overexpression of E6 and E7. The E6 and E7 proteins are thought to act as critical factors in cervical carcinogenesis by inactivating the two tumor suppressor proteins, p53 and Rb, which are commonly mutated in other human cancers.
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PMID:Molecular mechanism of carcinogenesis by human papillomavirus-16. 1072 54

The involvement of the tumor suppressor protein, p53, in thymic epithelial cell-induced apoptosis of CD4+8+ (double positive) thymocytes, was studied in an in vitro model consisting of a thymic epithelial cell line (TEC) and thymocytes. p53 expression was not augmented in double positive (DP) thymocytes upon co-culturing with TEC, although extensive apoptosis was observed. In the same cells, p53 expression was upregulated in response to low ionizing irradiation, which was accompanied with massive apoptosis. Moreover, TEC induced apoptosis in two DP thymomas, derived from p53(-/-) mice, and in a double positive thymoma clone expressing mutant p53. The extent and kinetics of TEC-induced apoptosis was not affected by the status of p53 in the thymocytes tested. We conclude that thymic epithelial cell-induced apoptosis of immature DP thymocytes is p53-independent and apparently, involves a different apoptotic pathway than that triggered by DNA damage.
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PMID:p53 and thymic 'death by neglect': thymic epithelial cell-induced apoptosis of CD4+8+ thymocytes is p53-independent. 1074 69

Previous studies have shown that the adenovirus type 5 (Ad5) E4orf6 gene product displays features of a viral oncoprotein. It initiates focal transformation of primary rat cells in cooperation with Ad5 E1 genes and confers multiple additional transformed properties on E1-expressing cells, including profound morphological alterations and dramatically accelerated tumor growth in nude mice. It has been reported that E4orf6 binds to p53 and, in the presence of the Ad5 E1B-55kDa protein, antagonizes p53 stability by targeting the tumor suppressor protein for active degradation. In the present study, we performed a comprehensive mutant analysis to assign transforming functions of E4orf6 to distinct regions within the viral polypeptide and to analyze a possible correlation between E4orf6-dependent p53 degradation and oncogenesis. Our results show that p53 destabilization maps to multiple regions within both amino- and carboxy-terminal parts of the viral protein and widely cosegregates with E4orf6-dependent acceleration of tumor growth, indicating that both effects are related. In contrast, promotion of focus formation and morphological transformation require only a carboxy-terminal segment of the E4 protein. Thus, these effects are completely independent of p53 stability, but may involve other interactions with the tumor suppressor. Our results demonstrate that at least two distinct activities contribute to the oncogenic potential of Ad5 E4orf6. Although genetically separable, both activities are largely mediated through a novel highly conserved, cysteine-rich motif and a recently described arginine-faced amphipathic alpha helix, which resides within a carboxy-terminal "oncodomain" of the viral protein.
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PMID:Two distinct activities contribute to the oncogenic potential of the adenovirus type 5 E4orf6 protein. 1079 92

Chronic infection with hepatitis B virus (HBV) is associated with development of hepatocellular carcinoma (HCC). The exact mechanism by which chronic infection with HBV contributes to onset of HCC is unknown. However, previous studies have implicated the HBV transactivator protein, HBx, in progression of HCC through its ability to bind the human tumor suppressor protein, p53. In this study, we have examined the ability of HBx to modify p53 regulation of the HCC tumor marker gene, alpha-fetoprotein (AFP). By utilizing in vitro chromatin assembly of DNA templates prior to transcription analysis, we have demonstrated that HBx functionally disrupts p53-mediated repression of AFP transcription through protein-protein interaction. HBx modification of p53 gene regulation is both tissue-specific and dependent upon the p53 binding element. Our data suggest that the mechanism by which HBx alleviates p53 repression of AFP transcription is through an association with DNA-bound p53, resulting in a loss of p53 interaction with liver-specific transcriptional co-repressors.
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PMID:Hepatitis B viral transactivator HBx alleviates p53-mediated repression of alpha-fetoprotein gene expression. 1084 85

p53 is a tumor suppressor protein that regulates many cellular processes including the cell cycle, DNA repair, and apoptosis. It also serves as a critical regulator of neuronal apoptosis in the central nervous system (CNS). To elucidate the role of p53 in the CNS, brain proteins of p53 knock-out mice (p53-/-) were analyzed by two-dimensional gel electrophoresis (2-DE) and compared with those from p53 wild type (p53+/+) mice. Six types of brain tissue (temporal cortex, cerebellum, hippocampus, striatum, olfactory bulb, and cervical spinal cord) and other control tissues (lung and blood) from 18-week-old non-stress-induced mice were analyzed. The morphology of brains from p53-/- mice appeared to be normal and identical to that of p53+/+ mice, although lungs showed diffuse tumors that may have been caused by p53 deficiency. Comparative 2-D gel analysis showed that, on average, 7 of 886 spots from brain tissue were p53-/- specific, whereas 12 of 1008 spots from lung tissue were p53-/- specific. N-terminal amino acid sequence was determined for p53-/- specific proteins. In all brain tissues from p53-/- mice, a newly identified mouse mitochondrial NADH-ubiquinone oxidoreductase 24 kDa subunit showed decreased expression, and apolipoprotein A1 acidic forms showed increased expression. In addition, brain-type creatine kinase B chain and tubulin beta-5 N-terminal fragment were increased in the p53-/- cerebellum, and a new protein in mouse, hydroxyacylglutathione hydrolase (glyoxalase II) was decreased in the temporal cortex of p53-/- mice. The alterations in protein expression identified in this study may imply a p53-related brain function. This is the first proteomic analysis on the p53-/- mouse brain, and further information based on this study will provide new insights into the p53 function in the CNS.
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PMID:Comparative analysis of brain proteins from p53-deficient mice by two-dimensional electrophoresis. 1087 Sep 73

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 p16(INK4a), an inhibitor of the cyclin D-dependent kinases. Reduction in levels of p27(Kip1) 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.
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PMID:The Pezcoller lecture: cancer cell cycles revisited. 1091 34

The tumor suppressor protein, p53, is part of the cell's emergency team that is called upon following cellular insult. How do cells sense DNA damage and other cellular stresses and what signal transduction pathways are used to alert p53? How is the resulting nuclear accumulation of p53 accomplished and what determines the outcome of p53 induction? Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. This review will focus on recent findings about how the p53 response may be activated following cellular stress.
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PMID:Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress. 1093 7

Although in Fischer-344 rats, aging has been shown to be associated with increased crypt cell production in the colonic mucosa, no information is available about the responsible intracellular mechanisms for the age-related rise in colonic mucosal cell proliferation. To determine whether cell cycling events are affected by aging, the present investigation examines the age-related changes in Cdk2 activity and the regulation of this process in the colonic mucosa. Colonic mucosae from 4-, 13- and 24-month-old Fischer-344 rats were assayed for Cdk2 activity and protein expression of Cdk2, cyclin D1 and E, as well as p21(Waf1/Cip1) (total and the fraction bound to Cdk2), p53 and phosphorylated Rb. Kinase activity and protein levels of Cdk2, as well as cyclin D1 concentration in the colonic mucosa, rose steadily with advancing age. However, the levels of cyclin E in the colonic mucosa were found to be higher in 24-month-old than 13-month-old rats, compared to their 4-month-old counterparts. On the other hand, levels of mucosal p21(Waf1/Cip1) (total and the fraction bound to Cdk2), one of the universal inhibitors of Cdks, were found to be lower in aged than in young rats. This was accompanied by a parallel decrease in mucosal p53, a tumor suppressor protein that is known to regulate p21(Waf1/Cip1). Additionally, we observed that the levels of phosphorylated Rb protein, a form which is involved in regulating progression of cells through the S phase, are increased in the colonic mucosa of 24-month-old rats, but not in 13-month-old animals, when compared with their 4-month-old counterparts. Our data suggest that, G(1) to S phase transition, as well as progression through the S phase of the cell cycle are accelerated in the colonic mucosa of aged rats.
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PMID:Aging enhances G(1) phase in the colonic mucosa of rats. 1093 4


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