Autoinhibitory regulation of p73 by Delta Np73 to modulate cell survival and death through a p73-specific target element within the Delta Np73 promoter.
p73 is a p53-related tumor suppressor but is also induced by oncogene products such as E2F-1, raising a question as to whether p73 is a tumor suppressor gene or oncogene. Unlike p53, p73 has several variants, including Delta Np73, which lacks the NH(2)-terminal transactivation domain. Although, in developing neurons, Delta Np73 is expressed abundantly and seems to inhibit the proapoptotic function of p53, the role of p73 and Delta Np73 and their regulatory mechanism in cell growth and differentiation are poorly understood. Here we report that p73, but not p53, directly activates the transcription of endogenous Delta Np73 by binding to the p73-specific target element located at positions -76 to -57 within the Delta Np73 promoter region. The activation of Delta Np73 promoter by p63 was marginal. Delta Np73 was associated with p73 alpha, p73 beta, and p53, as demonstrated by immunoprecipitation assays, and inhibited their transactivation activities when we used reporters of Mdm2, Bax, or Delta Np73 itself in SAOS-2 cells. Furthermore, induction or overexpression of Delta Np73 promoted cell survival by competing with p53 and p73 itself. Thus, our results suggest that the negative feedback regulation of p73 by its target Delta Np73 is a novel autoregulatory system for modulating cell survival and death.
Nakagawa
Takahito
T
Division of Biochemistry, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan.
Takahashi
Masato
M
Ozaki
Toshinori
T
Watanabe Ki
Ken-ichi
K
Todo
Satoru
S
Mizuguchi
Hiroyuki
H
Hayakawa
Takao
T
Nakagawara
Akira
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D015870:Gene Expression / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D004247:DNA; D002945:Cisplatin