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 tumor-suppressor function of p53 relies on its transcriptional activity, which is modulated by post-translational modifications and interactions with regulatory proteins. The prolyl isomerase Pin1 has a central role in transducing phosphorylation of p53 into conformational changes that affect p53 stability and function. We found that Pin1 is required for efficient loading of p53 on target promoters upon stress. In addition, Pin1 is recruited to chromatin by p53 and stimulates binding of the p300 acetyltransferase and consequent p53 acetylation. Accordingly, tumor-associated mutations at Pin1-binding residues within the p53 proline-rich domain hamper acetylation of p53 by p300. After phosphorylation of p53 at Ser46 triggered by cytotoxic stimuli, Pin1 also mediates p53's dissociation from the apoptosis inhibitor iASPP, promoting cell death. In tumors bearing wild-type p53, expression of Pin1 and iASPP are inversely correlated, supporting the clinical relevance of these interactions.
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PMID:The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. 1791 58

The peptidyl prolyl cis/trans isomerase Pin1 specifically binds phosphorylated Ser/Thr-Pro protein motifs and catalyzes the cis/trans isomerization of the peptide bond. Accumulating studies have revealed that Pin1 isomerase activity is regulated by its post-translational modifications, including phosphorylation and oxidation. Various transcription factors and regulators have been identified as substrates for Pin1. It enhances AP-1 activity via isomerization of both c-Jun and c-Fos for cellular proliferation and stabilizes the oncosuppressors p53 and p73 against DNA damage at the checkpoint. We demonstrated the association between the intracellular form of Notch1 (NIC) and Pin1 by analyzing Pin1/p53 double-knockout mice. Pin1 also regulates the post-transcriptional level of some cytokines, associated with asthma, that possess 3' untranslated region AU-rich elements (AREs) via interaction withAUF1, the nucleoprotein in the ARE-binding complex. Pin1 has been identified as the molecular partner of tau and amyloid precursor protein (APP), the key factors of Alzheimer's disease (AD). It interacts with the phosphorylated Thr-231 of tau and regulates its activity to bind microtubules. It further interacts with the phosphorylated Thr-668 of APP and affects its metabolism. Thus, Pin1 is probably involved in the pathogenesis of human diseases, including cancer, asthma, and AD, presenting an attractive target for future therapeutical drugs.
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PMID:Prolyl isomerase, Pin1: new findings of post-translational modifications and physiological substrates in cancer, asthma and Alzheimer's disease. 1796 33

P53 is a transcription factor also called the "cellular gatekeeper of genome" because it can induce cell cycle arrest in G1, apoptosis or affect DNA replication in response to DNA damage. Wild type p53 is localised in both the cytoplasm and nucleus of first trimester trophoblastic cells (CTB). Immunoblotting of CTB with different p53 antibodies led us to suggest that the N-terminus of p53 could be involved in the formation of high molecular weight complexes (HMWC), leading to the stabilisation of p53 in these cells. Here, we demonstrate that the N-terminus of p53 is involved in the formation of HMWC. Post-translational modifications of p53 seem to be responsible for its stabilisation and inactivation in CTB. We demonstrate that cis-trans isomerisation of proteins by the prolyl isomerase Pin1 is indispensable for the formation of these HMWC and stabilisation of p53. In contrast to observations made in other cells, in CTB, interaction of Pin1 and p53 does not involve phosphorylation of residues ser33, thr81 and ser315 of p53; on the contrary, phosphorylation of p53 leads to the rapid disappearance of some HMWC and destabilises p53. Moreover, decreasing HMWC or inhibiting Pin1 activity increases p53 activity towards its target genes MMP-9 and MMP-2, thus confirming the role of Pin-1 and these HMWC in the regulation of trophoblast invasiveness.
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PMID:Trophoblastic p53 is stabilised by a cis-trans isomerisation necessary for the formation of high molecular weight complexes involving the N-terminus of p53. 1831 40

Cell cycle regulators, such as cyclinD1 and p53, play major roles in the tumor response to radiation and chemotherapy in esophageal squamous cell carcinoma (SCC). Pin1-mediated prolyl-isomerization potentiates cell cycle progression and cell proliferation, including the regulation of cyclinD1 and p53. Herein, we investigated the effect of Pin1 in association with cyclinD1 and p53 on the sensitivity of esophageal SCC to chemoradiotherapy (CRT). The expression levels of Pin1, cyclinD1 and p53 were examined immunohistochemically in endoscopic biopsy specimens from 68 advanced esophageal SCC patients before CRT to determine whether their expression levels predicted the clinical effectiveness of CRT in individual cancers. Forty-six of the 68 patients (67.6%) had an effective response to CRT, whereas 22 patients (32.4%) had an ineffective response. There was no significant correlation between clinical responses and expression levels of cyclinD1 or p53. However, the clinical response of the high Pin1 expression group was significantly higher than that of the low expression group (P=0.0200). Moreover, our data indicate that the combined immunohistochemical evaluation of Pin1, cyclinD1 and p53 expression in pretreatment biopsy samples is a useful indicator of sensitivity to CRT in advanced esophageal SCC. Thus, Pin1 may influence cyclinD1 and p53 functions and predict CRT sensitivity.
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PMID:Expression of the prolyl isomerase Pin1 is a useful indicator of sensitivity to chemoradiotherapy in advanced esophageal squamous cell carcinoma. 1928 79

Cancer and Alzheimer's disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Abeta) and tau deposition. The possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders is discussed. Genetic polymorphisms, DNA methylation or other mechanisms that induce changes in activity of molecules with key roles in determining the decision to "repair and live"- or "die" could be involved in the pathogenesis of the two disorders. As examples, the role of p53, Pin1 and the Wnt signaling pathway are discussed as potential candidates that, speculatively, may explain inverse associations between AD and cancer.
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PMID:A common biological mechanism in cancer and Alzheimer's disease? 1951 1

Pin1, a conserved eukaryotic peptidyl-prolyl cis/trans isomerase, has important roles in cellular regulation. Because of its activity to switch the conformation of peptidyl-proline bonds in polypeptide chains, Pin1 operates as a binary switch, often in fate-determining pathways. Pin1 activity is usually controlled by substrate phosphorylation, but how Pin1 switches protein fates has been unclear. Here we show that Pin1 controls the degree of substrate ubiquitylation and thereby protein functions. We found that yeast Pin1 (Ess1) is essential for viability because it controls the NF-kappaB-related Spt23 transcription factor involved in unsaturated fatty-acid synthesis. High Pin1 activity results in low ubiquitylation of Spt23, which triggers Spt23 precursor processing and hence transcription factor activation. By contrast, decreased Pin1 activity leads to robust Spt23 polyubiquitylation and subsequent proteasomal degradation. Inhibition of Pin1 in mammalian cells changes the ubiquitylation status of the tumour suppressor protein p53 from oligoubiquitylation, which is known to trigger nuclear export, to polyubiquitylation, which causes nuclear p53 degradation. This suggests that the Pin1 activity is often translated into a fate-determining ubiquitylation switch, and that Pin1 may affect the degree of substrate ubiquitylation in other pathways as well.
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PMID:Prolyl isomerase Pin1 acts as a switch to control the degree of substrate ubiquitylation. 1959 89

Pin1 specifically catalyzes the cis/trans isomerization of phospho-Ser/Thr-Pro bonds and plays an important role in many cellular events through the effects of conformational change on the function of its biological substrates, including cell division cycle 25 C (Cdc25C), c-Jun and p53. Pin1 is overexpressed in many human cancer tissues, including breast, prostate and lung cancer. Its expression correlates with cyclin D1 levels, which contribute to cell transformation. Overexpression of Pin1 promotes tumor growth, while inhibition of Pin1 causes tumor cell apoptosis. Pin1 plays an important role in oncogenesis and therefore may serve as an effective anticancer target. Many inhibitors of Pin1 have been discovered, including several classes of designed inhibitors (alkene isosteres, reduced amides, indanyl ketones) and natural products (juglone, pepticinnamin E analogues, PiB and its derivatives obtained from a library screen). Pin1 inhibitors could be used as a novel type of anticancer drug by blocking cell cycle progression. Therefore, Pin1 represents a new diagnostic and therapeutic anticancer drug target.
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PMID:Pin1 as an anticancer drug target. 1989 Apr 97

Cell cycle progression requires changes in the activity or levels of a variety of key signaling proteins. G protein-coupled receptor kinase 2 (GRK2) plays a central role in G protein-coupled receptor regulation. Recent research is uncovering its involvement in additional cellular functions, but the potential role of GRK2 in the cell cycle has not been addressed. We report that GRK2 protein levels are transiently down-regulated during the G2/M transition by a mechanism involving CDK2-mediated phosphorylation of GRK2 at Serine670, which triggers binding to the prolyl-isomerase Pin1 and subsequent degradation. Prevention of GRK2 phosphorylation at S670 impedes normal GRK2 down-regulation and markedly delays cell cycle progression. Interestingly, we find that endogenous GRK2 down-regulation is prevented on activation of the G2/M checkpoint by doxorubicin and that stabilized GRK2 levels in such conditions inversely correlate with the p53 response and the induction of apoptosis, suggesting that GRK2 participates in the regulatory network controlling cell cycle arrest and survival in such conditions.
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PMID:G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. 2008 May 65

The peptidyl prolyl isomerase (Pin1) that catalyzes the isomerization of peptide bonds involving proline and phosphorylated serine/threonine/tyrosine and alters the conformation and differential folding has been implicated in the regulation and function of phosphorylated proteins including mitotic and cell cycle proteins viz. Cdc25c, Bcl2, p53 etc. DNA topoisomerase IIalpha is one of the nuclear enzymes that maintain the DNA topology and regulates nuclear transactions like chromatin segregation and mitosis. In the present studies, we have carried out in-silico investigations on the possibilities of pin1 interaction with topo IIalpha and its functional regulation. We found ten potential pin1 interacting sites within topo IIalpha, which were part of loop and/or low complexity regions except helix at S802 within the catalytic domain. Proline directed phosphorylation was found to be possible at 1354, 1361, 1393 positions by cdk. Change in dihedral angle (omega) to 0 degree at all potential pin1 interacting sites at 575, 602, 802 and 950 for cis conformation of peptide bond introduced significant structural change with higher potential energy. All-cis-topo IIalpha structure reveals that potential pin1 sites come closer to each other, perhaps forming a motif, thereby suggesting cooperative phenomenon to maintain higher potential energy conformation. The bio-informatic analysis of topo IIalpha showed that multisite interaction of pin1 is possible at all the predicted sites. However, a strong possibility of pin1 interaction exist within c-terminal at 1213, 1247, 1354, 1361, 1393 sites, which may lead to either alterations in localization or modification in the activity and perhaps stability of the enzyme.
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PMID:Interaction and structural modification of topoisomerase IIalpha by peptidyl prolyl isomerase, pin1: an in silico study. 2021 39

Cellular senescence limits the replicative capacity of normal cells and acts as an intrinsic barrier that protects against the development of cancer. Telomere shortening-induced replicative senescence is dependent on the ATM-p53-p21 pathway but additional genes likely contribute to senescence. Here, we show that the p53-responsive gene BTG2 plays an essential role in replicative senescence. Similar to p53 and p21 depletion, BTG2 depletion in human fibroblasts leads to an extension of cellular lifespan, and ectopic BTG2 induces senescence independently of p53. The anti-proliferative function of BTG2 during senescence involves its stabilization in response to telomere dysfunction followed by serum-dependent binding and relocalization of the cell cycle regulator prolyl isomerase Pin1. Pin1 inhibition leads to senescence in late-passage cells, and ectopic Pin1 expression rescues cells from BTG2-induced senescence. The neutralization of Pin1 by BTG2 provides a critical mechanism to maintain senescent arrest in the presence of mitogenic signals in normal primary fibroblasts.
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PMID:BTG2 antagonizes Pin1 in response to mitogens and telomere disruption during replicative senescence. 2056 34


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