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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

WW domains mediate protein-protein interactions through binding to short proline-rich sequences. Two distinct sequence motifs, PPXY and PPLP, are recognized by different classes of WW domains, and another class binds to phospho-Ser-Pro sequences. We now describe a novel Pro-Arg sequence motif recognized by a different class of WW domains using data from oriented peptide library screening, expression cloning, and in vitro binding experiments. The prototype member of this group is the WW domain of formin-binding protein 30 (FBP30), a p53-regulated molecule whose WW domains bind to Pro-Arg-rich cellular proteins. This new Pro-Arg sequence motif re-classifies the organization of WW domains based on ligand specificity, and the Pro-Arg class now includes the WW domains of FBP21 and FE65. A structural model is presented which rationalizes the distinct motifs selected by the WW domains of YAP, Pin1, and FBP30. The Pro-Arg motif identified for WW domains often overlaps with SH3 domain motifs within protein sequences, suggesting that the same extended proline-rich sequence could form discrete SH3 or WW domain complexes to transduce distinct cellular signals.
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PMID:A novel pro-Arg motif recognized by WW domains. 1074 24

DNA damage leads to stabilization and accumulation of p53, which plays a pivotal role in transcriptional activation of p21 and cell cycle arrest. The increase in p53 stability depends critically on its phosphorylation on serine/threonine residues, including those preceding a proline (Ser(P)/Thr-Pro). The Ser(P)/Thr-Pro moiety exists in the two distinct cis and trans conformations and their conversion is catalyzed specifically by the prolyl isomerase Pin1. Pin1 regulates the conformation and function of certain phosphorylated proteins and plays an important role in cell cycle regulation, oncogenesis, and Alzheimer's disease. However, nothing is known about the role of Pin1 in DNA damage. Here we found that DNA damage enhanced the interaction between Pin1 and p53, which depended on the WW domain in Pin1 and Ser(33/46)-Pro motifs in p53. Furthermore, Pin1 regulates the stability of p53 and its transcriptional activity toward the p21 promoter. As a result, p53 and p21 barely increased after DNA damage in Pin1 knock-out embryonic fibroblasts or in neoplastic cells depleted of Pin1. Moreover, Pin1 null cells displayed significant defects in cell cycle checkpoints induced by DNA damage. These results demonstrate a new role of Pin1 in regulating p53 function during DNA damage.
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PMID:Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. 1238 58

p53 is activated in response to various genotoxic stresses resulting in cell cycle arrest or apoptosis. It is well documented that DNA damage leads to phosphorylation and activation of p53 (refs 1-3), yet how p53 is activated is still not fully understood. Here we report that DNA damage specifically induces p53 phosphorylation on Ser/Thr-Pro motifs, which facilitates its interaction with Pin1, a member of peptidyl-prolyl isomerase. Furthermore, the interaction of Pin1 with p53 is dependent on the phosphorylation that is induced by DNA damage. Consequently, Pin1 stimulates the DNA-binding activity and transactivation function of p53. The Pin1-mediated p53 activation requires the WW domain, a phosphorylated Ser/Thr-Pro motif interaction module, and the isomerase activity of Pin1. Moreover, Pin1-deficient cells are defective in p53 activation and timely accumulation of p53 protein, and exhibit an impaired checkpoint control in response to DNA damage. Together, these data suggest a mechanism for p53 regulation in cellular response to genotoxic stress.
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PMID:The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. 1239 40

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

Phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major intracellular signaling mechanism. The phosphorylated Ser/Thr-Pro motifs in a certain subset of phosphoproteins are isomerized specifically by the peptidyl-prolyl cis-trans isomerase Pin1. This post-phosphorylation isomerization can lead to conformational changes in the substrate proteins and modulate their functions. Pin1 interacts with a number of mitotic phosphoproteins, and plays a critical role in mitotic regulation. Recent work indicates that Pin1 is overexpressed in many human cancers and plays an important role in oncogenesis. Pin1 regulates the expression of cyclin D1 by cooperating with Ras signaling and inhibiting the interaction of beta-catenin with the tumor suppressor APC and also directly stabilizing cyclin D1 protein. Furthermore, PIN1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. Pin1 is also a critical regulator of the tumor suppressor p53 during DNA damage response. Given its role in cell growth control and oncogenesis, Pin1 could represent a new anti-cancer target.
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PMID:Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer. 1257 Dec 75

Peptidyl-prolyl isomerases (PPIases) are chaperone enzymes which alter the peptide bond between a given amino acid and a proline, changing it from the cis to the trans conformation and vice versa. This modification can cause dramatic structural modifications which can affect the properties of targeted proteins. The ubiquitous PPIase Pin1, conserved from yeast to human, has been shown to be necessary for entry into mitosis. The yeast homologue, Ess1, is essential for cell survival. Pin1 possesses a WW domain which specifically recognizes pSer-Pro and pThr-Pro motifs in which the first amino acid is phosphorylated. Pin1 binds to many proteins implicated in cell cycle regulation (e.g. p53, Myt1, Wee1, and Cdc25C). Pin1 also targets tau, a protein forming part of hte neuronal cytoskeleton which is hyper-phosphorylated in patients suffering from Alzheimer's disease (AD). Pin1 could, therefore, be involved in the pathogenesis of Ad. Furthermore, Pin1 also binds two proteins involved in transcription: Rpb1, the largest subunit of RNA polymerase II and Spt5, a regulator of the elongation of transcription. Both theses proteins possess domains rich in S/T-P motifs which can be targeted by Pin1 when phosphorylated. Recent studies show that Pin1 modulates the dephosphorylation of some proteins by allowing trans-specific phosphatases to recognize their target after isomerization. This unexpected role might allow protein regulation via peptidyl-prolyl isomerase activity.
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PMID:[Unexpected roles of the peptidyl-prolyl cis/trans isomerase Pin1]. 1469 50

Activation of p73 upon genotoxic treatment triggers apoptosis of tumor cells lacking functional p53 and involves the activities of c-Abl and p300. Here, we demonstrate that conformational changes of p73 catalyzed by the prolyl isomerase Pin1 are crucial in this pathway. Lack of Pin1 reduces p73 stability, hampering its accumulation upon genotoxic stress. Indeed, we show that upon treatment with chemotherapeutic drugs c-Abl enhances the phosphorylation-dependent interaction between Pin1 and p73, and this in turn promotes p73 acetylation by p300. Consistently, the ability of c-Abl and p300 to increase p73 stability and transcriptional activity requires Pin1. As a consequence, Pin1 appears to be essential for activation of the apoptotic response by endogenous p73.
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PMID:Pin1 links the activities of c-Abl and p300 in regulating p73 function. 1517 57

The p53 protein averts tumor formation by preventing the proliferation of damaged cells. The presence of functional p53 is critical for efficient and proper cellular responses to a variety of stress conditions. Interestingly, p63 and p73, which are the homologous ancestors of p53, retain a broader set of activities than their progeny, particularly during early embryonic development. The link of these homologues to cancer and their effect on p53 tumor suppression is only beginning to be unravelled. The tight regulation of p53 is governed by the Mdm2 E3 ligase, but also by at least two other E3 ligases. Recent findings suggest fine-tuning of p53 regulation through changes in the ratio of p53 and Mdm2. This regulation of p53 is modulated by the Mdm2 homologue, Mdmx. Genetic studies reveal the critical role Mdmx plays in p53 regulation, although the mode of action is yet to be fully explored. The relief of p53 from this tight regulation is imperative in order for it to respond to stress signals. An intriguing player in this process is the prolyl isomerase Pin1, which induces a conformational change in p53, and more recently identified, also in p73, in response to DNA damage. This complex network of regulation emerges as a family affair. This wealth of knowledge has been translated into the development of novel anti-cancer strategies based on the p53 status in the cancer cell.
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PMID:p53 Regulation: a family affair. 1519 Jan 98

A recent paper shows that the peptidyl-prolyl isomerase Pin1 conformationally alters p73, promoting its acetylation by p300 in a c-Abl dependent manner. Given previous findings with p53, Pin1 may represent a common mediator linking proapoptotic cooperative activity of the p53 family members.
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PMID:The linchpin? Pin1 meets p73. 1519 53

The tumor suppressor p53 and the prolyl isomerase Pin1 are both highly connected proteins, lying at the crossroads between many signaling pathways that control cell proliferation and transformation. By catalyzing conformational changes in a large number of phosphorylated proteins, Pin1 has been implicated in the regulation of major cellular events, such as cell cycle progression, transcription, proliferation and differentiation. Recently, a role for Pin1 has emerged also in the DNA damage response, through modulation of p53 functions upon genotoxic stress. A further level of control has now been unveiled by showing that also the p53 sibling p73 requires Pin1 for its apoptotic activity.
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PMID:KeePin' the p53 family in good shape. 1525 34


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