UNIPROT:P04637 - FACTA Search

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)

CIP/KIP family proteins entitled p21(WAF1/CIP1) and p27(KIP1) have key positions in cell cycle regulation leading to an arrest of cell proliferation. They are supposed to enable a repair process of DNA damage. In several human tumors, a loss of these proteins is associated with poor clinical outcome. The role of these cell cycle regulators in tumors of salivary gland and paranasal sinus origin is still unclear. In this study it was intended to demonstrate and compare the expression of p21, p27, and p53 in benign and malignant tumors of salivary glands and paranasal sinuses. Protein expression was detected by conventional immunohistochemistry (IHC). Additionally, we performed tyramide signal amplified immunohistochemistry (TSA-IHC) for p21 and p53 levels. Nine adenoid cystic carcinomas, 5 adenocarcinomas, 4 cylindrical cell carcinomas, as well as 30 pleomorphic adenomas and 26 inverted papillomas, were studied. In 78% of all adenoid cystic carcinomas a complete loss of p27 expression could be identified, whereas 60% of the adenocarcinomas overexpressed the protein. The majority of cylindrical cell carcinomas showed distinct cytoplasmic accumulation of p27. All malignant tumors turned out to be positive for p21 after performing TSA-IHC, although 72% of those samples had shown weak to negative protein levels in conventional immunostaining. Immunohistochemical results of CIP/KIP proteins were compared to p53 expression as well as to main clinical parameters. The study sheds new light upon the role of CIP/KIP protein family in tumors of salivary glands and paranasal sinuses. Furthermore, it is the first description of p21 and p53 TSA-IHC in these tumor types.
...
PMID:Altered expression of cell cycle regulators p21, p27, and p53 in tumors of salivary glands and paranasal sinuses. 1587 Sep 26

Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase (AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells (HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB (PDGF-BB) and fetal calf serum (FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product (Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21(CIP) but not that of p27(KIP). Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on cell proliferation and the phosphorylation of Rb, suggesting that the effect of AICAR is mediated through the activation of AMPK. Cell cycle analysis in HASMCs showed that AICAR significantly increased cell population in G0/G1-phase and reduced that in S- and G2/M-phase, suggesting AICAR induced cell cycle arrest. AICAR increased both p53 protein and Ser-15 phosphorylated p53 in HASMCs, which were blocked by inhibition of AMPK. In isolated rabbit aortas, AICAR also increased Ser-15 phosphorylation and protein expression of p53 and inhibited Rb phosphorylation induced by FCS. These data suggest for the first time that AMPK suppresses VSMC proliferation via cell cycle regulation by p53 upregulation. Therefore, AMPK activation in VSMCs may be a therapoietic target for the prevention of vascular diseases.
...
PMID:Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. 1615 Oct 20

Retinoic acid receptor beta2 (RAR beta2) is often down-regulated during the multistep process to cervical cancer. In that way, its inhibitory function on the transcription factor AP-1, indispensable to maintain human papillomavirus (HPV) gene expression is relieved. Using HPV-18 positive HeLa cells as a model system, we show that ectopic expression of RAR beta2 is able to down-regulate HPV-18 transcription by selectively abrogating the binding of AP-1 to the viral regulatory region in a ligand-independent manner. This resulted in down-regulation of the viral mRNAs at the level of initiation of transcription. Decreased oncogene expression was accompanied by a re-induction of cell cycle inhibitory proteins such as p53, p21(CIP1), and p27(KIP) as well as by a cessation of cellular growth. Reduced transcriptional activity as a consequence of AP-1 reduction by selective c-Jun degradation apparently targets the HPV-18 regulatory region for epigenetic modification such as de novo methylation and nucleosomal condensation. This mechanism is otherwise counterbalanced by active and abundant viral transcription in malignant cells, because RAR beta2 itself becomes inactivated during cervical carcinogenesis. Hence, our study shows that the temporal co-existence of a potential repressor and viral oncoproteins is mutually exclusive and provides evidence of a cross-talk between a nuclear receptor, AP-1, and the epigenetic machinery.
...
PMID:Retinoic acid receptor beta silences human papillomavirus-18 oncogene expression by induction of de novo methylation and heterochromatinization of the viral control region. 1768 73

Accumulating evidences suggest that many molecules are working as inhibitors of proliferation in myeloma cells e.g., PTEN, mTOR(PI3-kinase signal molecules), p53, RB1, INK4 family and KIP/CIP family (cell cycle check point molecules), PF4 (inhibitor of angiogenesis). In this review, significance of these molecules in myeloma is summarized. Additionally, our finding of growth inhibitory effect by PU.1 is explained.
...
PMID:[Molecular mechanisms inhibiting proliferation of myeloma cells]. 1806 60

Multiple myeloma (MM) is an incurable plasma cell neoplasm. Pathogenesis involves upregulation of D-type cyclins and activation of oncogenes, but little is known about the role of tumor suppressor genes. Gene hypermethylation is an alternative mechanism of tumor suppressor gene inactivation. Various approaches have been used to elucidate the role of gene hypermethylation in MM, including a candidate gene approach, microarray approach for genes upregulated by hypomethylating agents, and a cancer pathway approach, which enables a comprehensive picture of the involvement of multiple tumor suppressor genes in MM. Based on the cancer pathway approach, the following data on the involvement of cell cycle control, intrinsic tumor suppressor, and cell signaling were derived. First, among the INK4 and CIP/KIP families of cyclin-dependent kinase inhibitors, only CDKN2B and CDKN2A are frequently hypermethylated. Second, methylation of SHP1 and soluble Wnt inhibitors is associated with constitutive activation of JAK/STAT and Wnt signaling. Importantly, downregulation of the signaling pathways can be restored by demethylation and re-expression of SHP1 and soluble Wnt inhibitors, which is potentially important therapeutically. Third, of the tumor suppressor genes involved in the DAPK/P14/HDM2/P53/Apaf-1 pathway, only DAPK is frequently methylated, which appeared to be an adverse prognostic factor to survival. Lastly, apart from being implicated in the progression from monoclonal gammopathy of unknown significance to MM, aberrant gene promoter methylation might also account for late disease progression in MM. Future studies are needed to delineate the biologic consequence of gene hypermethylation, the prognostic effect of gene methylation, and the possibility of hypomethylation therapy.
...
PMID:Gene hypermethylation in multiple myeloma: lessons from a cancer pathway approach. 1906 97

Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) is one of the essential latent antigens for primary B-cell transformation. Previous studies established that EBNA3C facilitates degradation of several vital cell cycle regulators, including the retinoblastoma (pRb) and p27(KIP) proteins, by recruitment of the SCF(Skp2) E3 ubiquitin ligase complex. EBNA3C was also shown to be ubiquitinated at its N-terminal residues. Furthermore, EBNA3C can bind to and be degraded in vitro by purified 20S proteasomes. Surprisingly, in lymphoblastoid cell lines, EBNA3C is extremely stable, and the mechanism for this stability is unknown. In this report we show that EBNA3C can function as a deubiquitination enzyme capable of deubiquitinating itself in vitro as well as in vivo. Functional mapping using deletion and point mutational analysis showed that both the N- and C-terminal domains of EBNA3C contribute to the deubiquitination activity. We also show that EBNA3C efficiently deubiquitinates Mdm2, an important cellular proto-oncogene, which is known to be overexpressed in several human cancers. The data presented here further demonstrate that the N-terminal domain of EBNA3C can bind to the acidic domain of Mdm2. Additionally, the N-terminal domain of EBNA3C strongly stabilizes Mdm2. Importantly, EBNA3C simultaneously binds to both Mdm2 and p53 and can form a stable ternary complex; however, in the presence of p53 the binding affinity of Mdm2 toward EBNA3C was significantly reduced, suggesting that p53 and Mdm2 might share a common overlapping domain of EBNA3C. We also showed that EBNA3C enhances the intrinsic ubiquitin ligase activity of Mdm2 toward p53, which in turn facilitated p53 ubiquitination and degradation. Thus, manipulation of the oncoprotein Mdm2 by EBNA3C potentially provides a favorable environment for transformation and proliferation of EBV-infected cells.
...
PMID:Epstein-Barr virus nuclear antigen 3C augments Mdm2-mediated p53 ubiquitination and degradation by deubiquitinating Mdm2. 1924 39

As cell cycle regulation is fundamental to the normal growth and development of the placenta, the aim of the present study was to determine the immunolocalizations of cell cycle related proteins, which have key roles in proliferation, differentiation and apoptosis during the development of the rat placenta. Here immunohistochemistry has been used to localize G1 cyclins (D1, D3, E), which are major determinants of proliferation, CIP/KIP inhibitors (p21, p27, p57), p53 as a master regulator and proliferating cell nuclear antigen in all cell types of the rat term placenta. The proportion of each cell type immunolabeled was counted. Cyclin D1 and cyclin D3 were present mostly in cells of the fetal aspect of the placenta, whereas the G1/S cyclin E was present only in the spongio- and labyrinthine trophoblast populations. Among the CIP/KIP inhibitors, p21 was present only in cells of the fetal aspect whereas p27 and p57 were found in all cell types studied. p53 was only found in a small proportion of cells with no co-localization of p53 and p21. The data suggest that the cells of the fetal side of the rat placenta still have some proliferation potential which is kept in check by expression of the CIP/KIP cell cycle inhibitors, whereas cells of the maternal aspect have lost this potential. Apoptosis is only marginal in the term rat placenta. In conclusion, proliferation and apoptosis in rat placental cells appears controlled mostly by the CIP/KIP inhibitors in late pregnancy.
...
PMID:Mapping of CIP/KIP inhibitors, G1 cyclins D1, D3, E and p53 proteins in the rat term placenta. 2178 82

The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor involved in the regulation of growth control and DNA damage response. We previously demonstrated that p57Kip2; a member of the CIP/KIP family of CDK (cyclin dependent kinase) inhibitors (CKI); is a direct target gene of HIC1 in quiescent cells. Here we show that ectopic expression of HIC1 in MDA-MB-231 cells or its overexpression in BJ-Tert fibroblasts induces decreased mRNA and protein expression of p21 (CIP1/WAF1) another member of this CKI family that plays essential roles in the p53-mediated DNA damage response. Conversely, knock-down of endogenous HIC1 in BJ-Tert through RNA interference up-regulates p21 in basal conditions and further potentiates this CKI in response to apoptotic etoposide-induced DNA damage. Through promoter luciferase activity and chromatin immunoprecipitation (ChIP), we demonstrate that HIC1 is a direct transcriptional repressor of p21. Thus, our results further demonstrate that HIC1 is a key player in the regulation of the DNA damage response.
...
PMID:Identification of p21 (CIP1/WAF1) as a direct target gene of HIC1 (Hypermethylated In Cancer 1). 2317 72

MiR-7 acts as a tumour suppressor in many cancers and abrogates proliferation of CHO cells in culture. In this study we demonstrate that miR-7 targets key regulators of the G1 to S phase transition, including Skp2 and Psme3, to promote increased levels of p27(KIP) and temporary growth arrest of CHO cells in the G1 phase. Simultaneously, the down-regulation of DNA repair-specific proteins via miR-7 including Rad54L, and pro-apoptotic regulators such as p53, combined with the up-regulation of anti-apoptotic factors like p-Akt, promoted cell survival while arrested in G1. Thus miR-7 can co-ordinate the levels of multiple genes and proteins to influence G1 to S phase transition and the apoptotic response in order to maintain cellular homeostasis. This work provides further mechanistic insight into the role of miR-7 as a regulator of cell growth in times of cellular stress.
...
PMID:MiR-7 triggers cell cycle arrest at the G1/S transition by targeting multiple genes including Skp2 and Psme3. 2376 7

p21^Waf1/Cip1, the cyclin-dependent kinase (CDK) inhibitor belonging to the KIP/CIP family, was initially regarded as a tumor suppressor protein because it was recognized as the chief mediator of p53-dependent cell cycle arrest elicited by DNA damage. Conversely, it has been proposed that p21^Waf1/Cip1 may also function as an oncogene because it can inhibit apoptosis. Thus, p21^Waf1/Cip1 is regarded as a protein with a dual behavior, as its expression might cause potential benefits or dangerous effects in breast cancer. Consequently, careful planning is required in targeting p21^Waf1/Cip1 expression for therapy of breast cancer patients. This review illustrates the discovery and mechanisms of induction of p21^Waf1/Cip1. Then, we focus on elucidating the paradoxical effect of p21^Waf1/Cip1 expression on human breast carcinogenesis and explaining how the subcellular localization (nuclear or cytoplasmic) of p21^Waf1/Cip1 has an impact on both determining its fate as either cell-growth inhibitor or antiapoptotic molecule and, its effect on clinicopathological factors and prognosis of breast cancer patients. Moreover, we explore how the pattern of the p21^Waf1/Cip1 could affect the responsiveness of human breast cancer to chemotherapy. Furthermore, the pharmacological approaches to target p21^Waf1/Cip1 expression for therapy of breast cancer are clarified.
...
PMID:p21^Waf1/Cip1: its paradoxical effect in the regulation of breast cancer. 3025 94

<< Previous 1 2 3 Next >>