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)

We used double staining histochemistry to investigate the relationship between apoptotic cell death and selective protein expression associated with DNA damage (p53, Bax, MDM2, Gadd45), DNA repair (PCNA) and cell cycle proteins (cyclin A, cyclin D, cdk2, cdk4) in rats (n = 6; control rats, n = 5) subjected to transient (2 h) middle cerebral artery occlusion (MCAo) and 46 h of reperfusion. Few apoptotic cells were detected in the non-ischemic hemisphere of control rats. In ischemic animals, scattered apoptotic cells were present in the ischemic core and clustered apoptotic cells were present and localized to the inner boundary zone of the ischemic core. Proteins were preferentially localized to the cellular cytoplasm of control rats and in the non-ischemic hemisphere of rats subjected to MCAo. However, after MCAo these proteins were expressed and were preferentially localized to nuclei within the ischemic lesion. DNA damage induced proteins (wt-p53 and p53-response proteins) were preferentially expressed within apoptotic cells after ischemia. DNA repair proteins and cell cycle proteins were preferentially expressed within morphologically intact cells and in reversibly damaged cells in the ischemic areas. The selective expression of proteins associated with DNA damage, DNA repair and cell cycle observed in morphologically intact cells, ischemic injured cells and apoptotic cells suggests a differential role for these proteins in cell survival and apoptosis after stroke.
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PMID:Apoptosis and protein expression after focal cerebral ischemia in rat. 931 3

Transgenic mice harboring the early genome from the human neurotropic JC virus, JCV, develop massive abdominal tumors of neural crest origin during 6-8 months after birth and succumb to death a few weeks later. The viral early protein, T-antigen, which possesses the ability to transform cells of neural origin, is highly expressed in the tumor cells. Immunoblot analysis of protein extract from tumor tissue shows high level expression of the tumor suppressor protein, p53, in complex with T-antigen. Expression of p21, a downstream target for p53, which controls cell cycle progression by regulating the activity of cyclins and their associated kinases during the G1 phase, is extremely low in the tumor cells. Whereas the level of expression and activity of cyclin D1 and its associated kinase, cdk6, was modest in tumor cells, both cyclin A and E, and their kinase partners, cdk2 and cdk4, were highly expressed and exhibited significant kinase activity. The retinoblastoma gene product, pRb, which upon phosphorylation by cyclins:cdk induces rapid cell proliferation, was found in the phosphorylated state in tumor cell extracts, and was detected in association with JCV T-antigen. The transcription factor, E2F-1, which dissociates from the pRb-E2F-1 complex and stimulates S phase-specific genes upon phosphorylation of pRb and/or complexation of pRb with the viral transforming protein, was highly expressed in tumor cells. Accordingly, high level expression of the E2F-1-responsive gene, proliferating cell nuclear antigen (PCNA), was detected in the tumor cells. These observations suggest a potential regulating pathway that, upon expression of JCV T-antigen, induces formation and progression of tumors of neural origin in a whole animal system.
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PMID:Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein. 932 27

The proliferation of most cells is strictly dependent on cell-matrix interactions, a phenomenon called anchorage dependence. Because tumor cells often are independent of this regulation, it is important to characterize the molecular pathways that control cellular proliferation after detachment of cells from their matrix. In this report, we investigated a possible role of p53 and one of its target genes, p21(waf1/cip1), as components of anchorage-dependent cell growth control. We found that p53 protein is rapidly activated upon the disruption of cellular attachment. This led to p21 transcriptional activation via two p53-binding sites in its promoter. Elevated p21 protein levels blocked transcription and activity of the cell cycle-regulator cyclin A, and cells became arrested in G1 of the cell cycle. Under the same conditions, fibroblasts from p53 knock-out mice did not activate p21 and did not down-regulate cyclin A expression but rather induced another cell cycle inhibitor, p27. Thus, our results characterize a chain of events, starting from the activation of p53 and proceeding via p21 to cyclin A, that is activated in response to the loss of cellular adherence. This p53-regulated pathway may constitute one of a few redundant systems to ensure proper cell control in multicellular organisms.
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PMID:Activation of p53-p21waf1 pathway in response to disruption of cell-matrix interactions. 936 Sep 84

MDM2 proto-oncogene expression is aberrant in many human tumors. Its normal role is to modulate the functions of p53. The N terminus of MDM2 interacts with p53, whereas the properties of the rest of the molecule are poorly understood. We show that MDM2 binds to the general transcription factor TFIID in vivo. The C-terminal Ring finger interacts with TAFII250/CCG1, and the central acidic domain interacts with TBP. Expression of MDM2 activates the cyclin A gene promoter but not c-fos, showing that the effects of MDM2 are specific. Deletion of the C-terminal region of MDM2 abolishes activation, showing that the C-terminal domain of MDM2 is functionally important. We found that increasing MDM2 expression to higher levels inhibits the cyclin A promoter. Inhibition appears to result from titration of general transcription factors because MDM2 overexpression inhibits c-fos as well as other promoters in vivo and basal transcription in vitro. The mechanisms of repression of the cyclin A and fos promoters appear to be different. Cyclin A repression is lost by deleting the C terminus, whereas that of c-fos is lost by removal of the acidic domain. These results reinforce the conclusion that the C terminus of MDM2 mediates effects on the cyclin A promoter. MDM2 transformed cells contain elevated levels of cyclin A mRNA, showing that activation occurs under physiological conditions. There is a positive correlation between MDM2 binding to TAFII250 and MDM2 activation of the cyclin A promoter. The C-terminal region of MDM2, which contains the Ring finger, interacts with TAFII250 and is required for regulation of the cyclin A promoter by MDM2. Our results link the activity of MDM2, a transforming protein implicated in many human tumors, with cyclin A, a regulator of the cell cycle.
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PMID:The MDM2 C-terminal region binds to TAFII250 and is required for MDM2 regulation of the cyclin A promoter. 938

Progressive deregulation of the cell-division cycle is thought to contribute to the establishment and progression of neoplasia. Previously, we have documented the in vivo inactivation of p16INK4A, an inhibitor of G1 cyclin-dependent kinases, in squamous cell carcinomas of the head and neck region. In the present study, we extend these findings by examining the expression and functional activity of cyclin-dependent kinases (CDKs) and their regulatory subunits using a model system of cell lines derived from squamous cell carcinomas. Increased activity of CDK4 and 6 was universal in tumor cells compared with normal keratinocytes, reflecting over-expression of either or both kinases. In contrast to other studies, over-expression of cyclin D1, a regulatory subunit of CDK4 and 6, was not observed. Increased activity of CDK2 was less frequent and was related to over-expression of cyclin A and/or E. All tumor cell lines showed increased expression of proliferating cell nuclear antigen compared to normal keratinocytes. Four SCC cell lines, including one tumor-metastasis pair derived from a single patient, failed to express the p15INK4B transcript. Western blot analysis of cell lysates revealed normal or reduced levels of p27KIP1 in tumor cells compared to normal keratinocytes. However, failure to express wild-type p53 was not reflected by lower levels of p21WAF1. Our data suggest that cell-cycle deregulation is likely to occur by multiple mechanisms during the genesis of head and neck squamous cell carcinomas. Furthermore, p16INK4A is likely to be the primary target for inactivation on chromosome 9p21 in these tumors as p15INK4B loss occurs less frequently.
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PMID:Altered expression and activity of G1/S cyclins and cyclin-dependent kinases characterize squamous cell carcinomas of the head and neck. 938 71

Cell cycle arrest in G1 in response to ionizing radiation or senescence is believed to be provoked by inactivation of G1 cyclin-cyclin-dependent kinases (Cdks) by the Cdk inhibitor p21(Cip1/Waf1/Sdi1). We provide evidence that in addition to exerting negative control of the G1/S phase transition, p21 may play a role at the onset of mitosis. In nontransformed fibroblasts, p21 transiently reaccumulates in the nucleus near the G2/M-phase boundary, concomitant with cyclin B1 nuclear translocation, and associates with a fraction of cyclin A-Cdk and cyclin B1-Cdk complexes. Premitotic nuclear accumulation of cyclin B1 is not detectable in cells with low p21 levels, such as fibroblasts expressing the viral human papillomavirus type 16 E6 oncoprotein, which functionally inactivates p53, or in tumor-derived cells. Moreover, synchronized E6-expressing fibroblasts show accelerated entry into mitosis compared to wild-type cells and exhibit higher cyclin A- and cyclin B1-associated kinase activities. Finally, primary embryonic fibroblasts derived from p21-/- mice have significantly reduced numbers of premitotic cells with nuclear cyclin B1. These data suggest that p21 promotes a transient pause late in G2 that may contribute to the implementation of late cell cycle checkpoint controls.
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PMID:Nuclear accumulation of p21Cip1 at the onset of mitosis: a role at the G2/M-phase transition. 941 1

Cyclins are essential proteins in cell cycle control, and their deranged expression has been reported to be associated with malignant transformation. Involvement of cyclins in the development of endometrioid carcinomas of the endometrium was studied immunohistochemically using antibodies against both cyclin A and tumor suppressor gene product p53, and their expression was compared with that of Ki-67 antigen. Sixty-two cases of endometrial endometrioid carcinoma and 20 cases of normal endometrium (10 proliferative and 10 secretory phase) were examined. Of the 62 endometrioid carcinomas, atrophic endometrium and hyperplasia were found adjacent to the cancers in 30 and 19 cases respectively. Cyclin A was expressed in < 1% of the glandular cells of normal endometrium in the proliferative phase and in hyperplasia, but was negligible in normal secretory phase and atrophic endometrium. p53 was almost always negative in normal endometrium and hyperplasia. Of the 62 endometrioid carcinomas, 12 tumors (19.4%) overexpressed cyclin A and 21 tumors (33.8%) overexpressed p53 (positive cells > 1%). Cyclin A and p53 were more frequently expressed in poorly differentiated tumors than in well differentiated tumors (cyclin A, p = 0.002; p53, p = 0.016). In addition, cyclin A-positive cells were topographically related to those cells positive for p53 as well as Ki-67. In conclusion, the abnormal expression of cyclin A and p53 is associated with high-grade endometrial endometrioid carcinomas.
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PMID:Immunohistochemical detection of cyclin A with reference to p53 expression in endometrial endometrioid carcinomas. 942 Oct 74

B-Myb belongs to a family of related transcription factors which share a unique DNA binding domain. B-Myb plays an important role in regulation of the cell cycle. Its expression is upregulated by the human papilloma virus HPV16 E7 oncoprotein. Overexpression of B-Myb can bypass p53-mediated cell cycle arrest. The founding member of the myb gene family, c-Myb, and A-Myb are involved in hematopoiesis and neurogenesis, respectively, and are both activators of gene transcription. Whether B-Myb is a transactivator or a repressor, however, has remained a matter of discussion. We reviewed the transactivation potential of B-Myb in yeast, taking advantage of the fact that inducible gene activation is an evolutionarily conserved process. By mutational analysis we localized a conserved activation domain in B-Myb. In vertebrate cells the transactivation potential of B-Myb is concealed by the C-terminal part of the protein. We show that the cell cycle regulators cyclin A and cyclin E activate B-Myb by eradicating the inhibition mediated by its carboxy-terminus. Our data suggest that in vertebrates the trans-activating function of B-Myb is regulated during the cell cycle and link Myb functions to cell cycle progression.
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PMID:B-Myb, a repressed trans-activating protein. 942 11

Apoptosis was promoted at the nonpermissive temperature in some temperature-sensitive (ts) mutant strains of mouse FM3A cells deficient in initiation of DNA replication. We examined expression of cell cycle regulation genes in the four ts mutant strains and found that two strains, tsFT107 and tsFT111, exhibited marked accumulation of p53 protein by a posttranscriptional mechanism at 16 h after temperature up-shift. These two strains also exhibited high levels of p21 mRNA expression, repression of cyclin A and D1 mRNAs, and obvious accumulation of underphosphorylated retinoblastoma protein. Only these two strains died by apoptosis at day 3 after up-shift, although no change was observed in the level of bax mRNA. These results suggest the existence of two types of responses after temperature up-shift in the four temperature-sensitive cell strains of the initiation of DNA replication: one type directs inappropriate DNA replication that then may produce endogenous DNA damage, p53-mediated cell cycle arrest, and subsequent apoptosis, while the other type exhibits only the p53-independent cell cycle arrest.
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PMID:Apoptosis was promoted at a nonpermissive temperature in DNA replication-defective temperature-sensitive mutants of mouse FM3A cells. 947 39

Anti-idiotype (anti-Id) antibody can induce tumor dormancy in a murine B lymphoma, BCL1, by its ability to induce cell cycle arrest and apoptosis (negative signaling). In human B lymphoma, there is accumulating evidence that the antitumor effect of anti-Id or several other B cell-reactive antibodies relates to their ability to act as agonists rather than conventional effector antibodies. In this study, we sought to elucidate the role of cyclins, cyclin-dependent kinases (CDKs), and their inhibitors in anti-IgM-induced cell cycle arrest to better understand the mechanisms underlying cancer dormancy. To accomplish this, we have performed in vitro studies with a human lymphoma cell line (Daudi) because its response to anti-Id (or anti-IgM) is similar to that of a BCL1 cell line, more reagents are available, and the results would be particularly pertinent to therapy of human B cell lymphomas. Our results show that cross-linking of membrane IgM on Daudi cells induces an arrest late in G1 and prevents pRb from becoming phosphorylated. The G1 arrest is correlated with an induction of the CDK inhibitor p21 and reduced CDK2 activity, although the level of CDK2 protein was not changed. Coprecipitation of CDK2 with p21 in anti-IgM-treated cells and the unchanged level of cyclin E suggest that p21 is responsible for the reduction of CDK2 activity and therefore blockade of the cell cycle. The induction of p21 was not accompanied by changes in p53 levels. As a result of the G1 block, cyclin A levels sharply declined by 24 h after anti-IgM treatment. There was no evidence for involvement of CDK4 or CDK6 in the blockade. These results provide evidence that membrane IgM cross-linking on Daudi cells induces expression of p21 and a subsequent inhibition of the cyclin E-CDK2 kinase complex resulting in a block to pRb phosphorylation and cell cycle arrest late in G1.
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PMID:Cancer dormancy: role of cyclin-dependent kinase inhibitors in induction of cell cycle arrest mediated via membrane IgM. 948 22


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