Physical and functional interaction between p53 and the Werner's syndrome protein.
Werner's syndrome is a human autosomal recessive disorder leading to premature aging. The mutations responsible for this disorder have recently been localized to a gene (WRN) encoding a protein that possesses DNA helicase and exonuclease activities. Patients carrying WRN gene mutations exhibit an elevated rate of cancer, accompanied by increased genomic instability. The latter features are also characteristic of the loss of function of p53, a tumor suppressor that is very frequently inactivated in human cancer. Moreover, changes in the activity of p53 have been implicated in the onset of cellular replicative senescence. We report here that the WRN protein can form a specific physical interaction with p53. This interaction involves the carboxyl-terminal part of WRN and the extreme carboxyl terminus of p53, a region that plays an important role in regulating the functional state of p53. A small fraction of WRN can be found in complex with endogenous p53 in nontransfected cells. Overexpression of WRN leads to augmented p53-dependent transcriptional activity and induction of p21(Waf1) protein expression. These findings support the existence of a cross-talk between WRN and p53, which may be important for maintaining genomic integrity and for preventing the accumulation of aberrations that can give rise to premature senescence and cancer.
Blander
G
G
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Kipnis
J
J
Leal
J F
JF
Yu
C E
CE
Schellenberg
G D
GD
Oren
M
M
D019588:Aging, Premature / Q000209:etiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D006801:Humans; D009369:Neoplasms / Q000209:etiology; D011485:Protein Binding; D053484:RecQ Helicases; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014898:Werner Syndrome / Q000235:genetics; D000071657:Werner Syndrome Helicase
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase