Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumour suppressor p53 is important in the cell decision to either arrest cell cycle progression or induce apoptosis in response to a variety of stimuli. p53 post-translational modifications and association with other proteins have been implicated in the regulation of its stability and transcriptional activities. Here we report that, on DNA damage, p53 interacts with Pin1, a peptidyl-prolyl isomerase, which regulates the function of many proteins involved in cell cycle control and apoptosis. The interaction is strictly dependent on p53 phosphorylation, and requires Ser 33, Thr 81 and Ser 315. On binding, Pin1 generates conformational changes in p53, enhancing its transactivation activity. Stabilization of p53 is impaired in UV-treated Pin1(-/-) cells owing to its inability to efficiently dissociate from Mdm2. As a consequence, a reduced p53-dependent response was detected in Pin1(-/-) cells, and this correlates with a diminished transcriptional activation of some p53-regulated genes. Our results suggest that, following stress-induced phosphorylation, p53 needs to form a complex with Pin1 and to undergo a conformational change to fulfil its biological roles.
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PMID:The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. 1239 40

Peptidyl-proline isomerase (Pin1) is able to trigger some conformationally important change in the p53 protein: there is notable protection by p53 (tumour suppressor protein) of human cells that prevents their entry into the carcinogenesis-committed routeway. Pin1 controls the ready (low energy change) equilibrium between the cis and trans distinctive folding configurations differentially at a proline residue: this amino acid residue in proteins is unique in bending sharply its peptide chain (to 90 degrees change): in the cis rather than trans orientation with respect to the peptide bond to residue X "upstream" linked as XCONHR. Moreover p53 protein can arrest a cell cycle progression (or trigger apoptosis) by acting as a transcription factor to nuclear DNA acting at p53 nuclear responsive element controlling a larger number of genes that produce proteins that stop cell growth or stimulate apoptosis, in stressed cells. Oxidative stress by reactive oxygen species (ROS) is carcinogenic but also stops cell growth and triggers apoptosis, Cu-SOD removes ROS (see figure). Could superoxide dismutase (Cu-SOD), therefore, provide the DNA-damage direct second route (first route is binding of Pin1) in DNA-damaged cells to p53 activation? The p53 protein that prevents carcinogenesis is activated by Pin1. In addition, this p53 tumour suppressor protein is activated by Cu-SOD.
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PMID:p53 Protein is activated by Pin1: and also by Cu-SOD prion-like enzyme. 1589 13

Expression of the c-Myc proto-oncoprotein is tightly regulated in normal cells. Phosphorylation at two conserved residues, threonine58 (T58) and serine62 (S62), regulates c-Myc protein stability. In cancer cells, c-Myc can become aberrantly stabilized associated with altered T58 and S62 phosphorylation. A complex signalling cascade involving GSK3beta kinase, the Pin1 prolyl isomerase, and the PP2A-B56alpha phosphatase controls phosphorylation at these sites. We report here a novel role for the tumour suppressor scaffold protein Axin1 in facilitating the formation of a degradation complex for c-Myc containing GSK3beta, Pin1, and PP2A-B56alpha. Although knockdown of Axin1 decreases the association of c-Myc with these proteins, reduces T58 and enhances S62 phosphorylation, and increases c-Myc stability, acute expression of Axin1 reduces c-Myc levels and suppresses c-Myc transcriptional activity. Moreover, the regulation of c-Myc by Axin1 is impaired in several tested cancer cell lines with known stabilization of c-Myc or loss of Axin1. This study provides critical insight into the regulation of c-Myc expression, how this can be disrupted in three cancer types, and adds to our knowledge of the tumour suppressor activity of Axin1.
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PMID:The Axin1 scaffold protein promotes formation of a degradation complex for c-Myc. 1926 62

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