Multiple stress signals induce p73beta accumulation.
Although p73 is a structural and functional homologue of the tumor-suppressor gene p53, it is not mutated in many human cancers as p53. Besides, p73 was shown to be activated by only a subset of signals that activate p53, such as gamma-irradiation and cisplatin, but not by other common genotoxic stress-inducing agents such as ultraviolet (UV) irradiation, although many of these signals are also capable of inducing p53-independent cell death. Using a p73-specific antibody, we confirmed that c-Abl is required for cisplatin-induced p73 upregulation, and further demonstrate that the p73 protein is upregulated by UV irradiation and other stress stimuli including sorbitol, hydrogen peroxide, nocodazol, and taxol. These stress signals upregulate both p73 mRNA and increases the stability of p73, indicating that p73 is regulated transcriptionally and posttranslationally. Cells stably expressing the dominant-negative p73 inhibitor protein (p73DD) and p73(-/-) fibroblasts are more resistant than control cells to apoptosis induced by these stress signals, suggesting that p73 contributes to apoptosis induction. Together, the data demonstrate that several stress signals can signal to p73 in vivo, which raises the possibility of eradicating cancers with an unmutated p73 gene by activating them with stress-inducing agents or their mimetics.
Lin
Kai Wei
KW
Laboratory of Molecular Carcinogenesis, National Cancer Centre, 11 Hospital, Drive, Singapore 169610, Singapore.
Nam
Shin Yuen
SY
Toh
Wen Hong
WH
Dulloo
Iqbal
I
Sabapathy
Kanaga
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D019556:COS Cells; D002457:Cell Extracts / Q000276:immunology; D002522:Chlorocebus aethiops; D002945:Cisplatin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D002457:Cell Extracts; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D016315:Proto-Oncogene Proteins c-abl; D017239:Paclitaxel; D002945:Cisplatin