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 average length of telomere repeats at the ends of chromosomes in most normal human somatic cells has been found to decrease by 50-200 base pairs with each cell division. The loss of telomere repeats has been causally linked to replicative senescence by the demonstration that overexpression of the enzyme telomerase can result in the elongation or maintenance of telomeres and immortalization of somatic cells with a diploid and apparently normal karyotype. Major questions that remain are related to the actual mechanism by which telomere shortening induces replicative senescence and the importance of telomere shortening and replicative senescence in the homeostasis of cells in renewal tissues and aging. This perspective is concerned with the consequences of telomere shortening at individual chromosomes in individual cells. Experimental evidence indicates that short telomeres accumulate prior to senescence and that replicative senescence is not triggered by the first telomere to reach a critical minimal threshold length. These observations are compatible with limited repair of short telomeres by telomerase-dependent or telomerase-independent DNA repair pathways. Deficiencies in telomere repair may result in accelerated senescence and aging as well as genetic instability that facilitates malignant transformation. Examples of molecules that may have a role in the repair of telomeric DNA prior to replicative senescence include ATM, p53, PARP, DNA-PK, Ku70/80, the human hRad50-hMre11-p95 complex, BRCA 1 and 2 and the helicases implicated in Bloom's and Werner's syndrome.
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PMID:Repair of telomeric DNA prior to replicative senescence. 1098 22

Mutations in the p53 tumor-suppressor gene promote increased genomic instability and cancer. Mutations in the WRN gene, encoding a DNA helicase, underlie the segmental progeroid Werner syndrome (WS). WS is also associated with increased genomic instability and elevated cancer risk. The p53 and WRN proteins can engage in direct protein-protein interactions. We report that excess WRN elicits increased cellular p53 levels and potentiates p53-mediated apoptosis. Importantly, cells derived from WS patients exhibit an attenuated and delayed induction of p53 by UV or by the topoisomerase I inhibitor camptothecin. These results suggest that WRN may participate in the activation of p53 in response to certain types of DNA damage. Furthermore, the failure to induce p53 effectively may contribute to enhanced genomic instability and elevated cancer risk in WS patients.
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PMID:The Werner syndrome protein contributes to induction of p53 by DNA damage. 1102 99

The aging process has multiple causes. However, there is now substantial evidence consistent with the hypothesis that (i) all normal mammalian somatic cells have a finite capacity to replicate and (ii) that gradual cell turnover throughout the lifespan of a mammal eventually exhausts this finite capacity. This results in a gradual accumulation of senescent (irreversibly post-mitotic) cells with increasing age. These cells display a radically different phenotype to their growing counterparts, which has the potential to compromise tissue function. Perhaps the best evidence for this is seen in Werner's syndrome, a rare genetic disease, in which patients display most of the features of accelerated aging, together with a profoundly compromised replicative lifespan in certain tissue lineages. Several classes of human cells are now known to count divisions by monitoring the progressive attrition of chromosomal ends (telomeres), leading to the activation of a p53-p21waf-dependent G1 checkpoint. Ectopic expression of telomerase has been shown to prevent senescence in several cell types and offers the potential for interventions in the aging process based on tissue engineering, gene therapy or homeografts. However, this telomere-driven senescence mechanism seems to be absent from rodents, which use telomere-independent means (perhaps based upon p14arf) to count divisions. Similar senescence pathways are now being reported in humans, and this, coupled with the demonstration of tissue-specific telomeric loss rates, has the potential to render strategies based on the use of telomerase dependent on the characteristics of the target tissue. Werner's syndrome may provide strong clues regarding the potential limitations and prospects of such future treatments.
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PMID:Telomerase and the cellular lifespan: implications of the aging process. 1120 23

Deficiency in a helicase of the RecQ family is found in at least three human genetic disorders associated with cancer predisposition and/or premature ageing. The RecQ helicases encoded by the BLM, WRN and RECQ4 genes are defective in Bloom's, Werner's and Rothmund-Thomson syndromes, respectively. Cells derived from individuals with these disorders in each case show inherent genomic instability. Recent studies have demonstrated direct interactions between these RecQ helicases and human nuclear proteins required for several aspects of chromosome maintenance, including p53, BRCA1, topoisomerase III, replication protein A and DNA polymerase delta. Here, we review this network of protein interactions, and the clues that they present regarding the potential roles of RecQ family members in DNA repair, replication and/or recombination pathways.
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PMID:DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. 1125 7

Werner syndrome is an autosomal recessive disorder characterized by genomic instability and by the premature onset of a number of age-related diseases, including malignancy. To assess a potential collaboration between p21 or p53 cell cycle regulators and Wrn proteins, Wrn mutant mice were created and mated with p21 or p53 null mice to generate double mutants. The p21 null/Wrn mutant mice did not show an acceleration of tumorigenesis during the first year of life, suggesting that the p53-dependent G1-S cell cycle checkpoint (which operates via p21) is not involved in Wrn-abetted tumor suppression. In contrast, the p53 null/Wrn mutant mice were particularly remarkable with respect to the rapidity with which they developed tumors. These mice were also distinguished by the variety of tumors they developed compared to those that developed in p53 null mice. Such data suggest a genetic interaction between p53 and Wrn in which loss of Wrn provokes a more variable p53 response unrelated to its role in the G1-S cell cycle checkpoint.
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PMID:Tumorigenic effect of nonfunctional p53 or p21 in mice mutant in the Werner syndrome helicase. 1128 Jul 29

Werner syndrome (WS) is an autosomal recessive disease manifested by the premature onset of age-related phenotypes, including diseases such as atherosclerosis and cancer. This mimicry of normal aging with the possible exception of central nervous system manifestations has made it a focus of recent molecular studies on the pathophysiology of aging. In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions. The WS gene product (WRN) is a DNA helicase belonging to the RecQ family, but is unique within this family in that it also contains an exonuclease activity. In addition to unwinding double-stranded DNA, WRN helicase is able to resolve aberrant DNA structures such as G4 tetraplexes, triplexes and 4-way junctions. Concordant with this structure-specificity, WRN exonuclease preferentially hydrolyzes alternative DNA that contains bubbles, extra-helical loops, 3-way junctions or 4-way junctions. WRN has been shown to bind to and/or functionally interact with other proteins, including replication protein A (RPA), proliferating cell nuclear antigen (PCNA), DNA topoisomerase I, Ku 86/70, DNA polymerase delta and p53. Each of these interacting proteins is involved in DNA transactions including those that resolve alternative DNA structures or repair DNA damage. The biochemical activities of WRN and the functions of WRN associated proteins suggest that in vivo WRN resolves DNA topological or structural aberrations that either occur during DNA metabolic processes such as recombination, replication and repair, or are the outcome of DNA damage.
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PMID:Unwinding the molecular basis of the Werner syndrome. 1134 59

The Bloom syndrome (BS) protein, BLM, is a member of the RecQ DNA helicase family that also includes the Werner syndrome protein, WRN. Inherited mutations in these proteins are associated with cancer predisposition of these patients. We recently discovered that cells from Werner syndrome patients displayed a deficiency in p53-mediated apoptosis and WRN binds to p53. Here, we report that analogous to WRN, BLM also binds to p53 in vivo and in vitro, and the C-terminal domain of p53 is responsible for the interaction. p53-mediated apoptosis is defective in BS fibroblasts and can be rescued by expression of the normal BLM gene. Moreover, lymphoblastoid cell lines (LCLs) derived from BS donors are resistant to both gamma-radiation and doxorubicin-induced cell killing, and sensitivity can be restored by the stable expression of normal BLM. In contrast, BS cells have a normal Fas-mediated apoptosis, and in response to DNA damage normal accumulation of p53, normal induction of p53 responsive genes, and normal G(1)-S and G(2)-M cell cycle arrest. BLM localizes to nuclear foci referred to as PML nuclear bodies (NBs). Cells from Li-Fraumeni syndrome patients carrying p53 germline mutations and LCLs lacking a functional p53 have a decreased accumulation of BLM in NBs, whereas isogenic lines with functional p53 exhibit normal accumulation. Certain BLM mutants (C1055S or Delta133-237) that have a reduced ability to localize to the NBs when expressed in normal cells can impair the localization of wild type BLM to NBs and block p53-mediated apoptosis, suggesting a dominant-negative effect. Taken together, our results indicate both a novel mechanism of p53 function by which p53 mediates nuclear trafficking of BLM to NBs and the cooperation of p53 and BLM to induce apoptosis.
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PMID:Functional interaction of p53 and BLM DNA helicase in apoptosis. 1139 66

Werner syndrome (WS) is characterized by the early onset of symptoms of premature aging, cancer, and genomic instability. The molecular basis of the defects is not understood but presumably relates to the DNA helicase and exonuclease activities of the protein encoded by the WRN gene that is mutated in the disease. The attenuation of p53-mediated apoptosis in WS cells and reported physical interaction between WRN and the tumor suppressor p53 suggest that p53 and WRN functionally interact in a pathway necessary for the normal cellular response. In this study, we have demonstrated that p53 inhibits the exonuclease activity of the purified full-length recombinant WRN protein. p53 did not have an effect on a truncated amino-terminal WRN fragment that retains exonuclease activity but lacks the physical interaction domain for p53 located in the carboxyl terminus. Two naturally occurring p53 mutants found in human cancer displayed a reduced ability to inhibit WRN exonuclease activity. In cells arrested in S phase with hydroxyurea, WRN exits the nucleolus and colocalizes with p53 in the nucleoplasm. The regulation of WRN function by p53 is likely to play an important role in the maintenance of genomic integrity and prevention of cancer and other clinical symptoms associated with WS.
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PMID:p53 Modulates the exonuclease activity of Werner syndrome protein. 1142 32

Mutations in several DExH-containing DNA helicases, including XPD, XPB, WRN, and BLM, are associated with rare familial cancer syndromes characterized by genomic instability and cancer susceptibility. Known cellular activities of these helicases include DNA replication, repair, recombination, and/or transcription. The p53 tumor suppressor is a regulator of cellular responses to stress, and is biochemically involved in the induction of cell-cycle arrest, apoptosis and DNA repair, all of which contribute to maintenance of genomic integrity. Physical and functional interactions of p53 with DExH-containing DNA helicases have been described. We propose that such interactions could be compromised in inherited disorders and contribute to their cancer susceptibility. In particular, the role of DNA helicases in p53-mediated apoptotic pathways is reviewed.
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PMID:p53-mediated apoptosis and genomic instability diseases. 1176 63

Two systems are essential in humans for genome integrity, DNA repair and apoptosis. Cells that are defective in DNA repair tend to accumulate excess DNA damage. Cells defective in apoptosis tend to survive with excess DNA damage and thus allow DNA replication past DNA damages, causing mutations leading to carcinogenesis. It has recently become apparent that key proteins which contribute to cellular survival by acting in DNA repair become executioners in the face of excess DNA damage. Five major DNA repair pathways are homologous recombinational repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR). In each of these DNA repair pathways, key proteins occur with dual functions in DNA damage sensing/repair and apoptosis. Proteins with these dual roles occur in: (1) HRR (BRCA1, ATM, ATR, WRN, BLM, Tip60 and p53); (2) NHEJ (the catalytic subunit of DNA-PK); (3) NER (XPB, XPD, p53 and p33(ING1b)); (4) BER (Ref-1/Ape, poly(ADP-ribose) polymerase-1 (PARP-1) and p53); (5) MMR (MSH2, MSH6, MLH1 and PMS2). For a number of these dual-role proteins, germ line mutations causing them to be defective also predispose individuals to cancer. Such proteins include BRCA1, ATM, WRN, BLM, p53, XPB, XPD, MSH2, MSH6, MLH1 and PMS2.
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PMID:DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. 1205 32


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