Functional implication of p73 protein stability in neuronal cell survival and death.
p73, a newly identified member of p53 family, locates at human chromosome 1p36.2-3, a region which is frequently deleted in a wide variety of human tumors including neuroblastoma. p73 is induced to be accumulated in response to a subset of DNA damaging agents such as cisplatin, and thereby promoting G1/S cell cycle arrest and/or apoptosis. Since the expression levels of p73 are kept extremely low under normal conditions, stabilization of p73 is critical for its effects on cell growth inhibition and apoptosis. Indeed, p73 is induced at protein level in SH-SY5Y neuroblastoma cells exposed to cisplatin. Several lines of evidence indicate that stress-induced post-translational modifications of p73 such as phosphorylation and acetylation lead to a marked extension of its half-life. p73 stability is regulated at least in part by proteasome-dependent degradation pathway, however, MDM2 which mediates ubiquitination and subsequent degradation of p53 by the 26S proteasome, does not promote the proteolytic degradation of p73, implying that the protein stability of p73 is regulated through a pathway distinct from that of p53. Although little is known about the regulation of p73 turnover, we are now beginning to understand the regulatory mechanisms by which p73 is induced to be stabilized in response to apoptotic stimuli, and exerts its pro-apoptotic activity. In this review, we discuss about the cellular proteins implicated in the stability control of p73.
Ozaki
Toshinori
T
Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Hosoda
Mitsuchika
M
Miyazaki
Kou
K
Hayashi
Syunji
S
Watanabe
Ken-Ichi
K
Nakagawa
Takahito
T
Nakagawara
Akira
A
D016923:Cell Death; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D009447:Neuroblastoma / Q000473:pathology*; D009474:Neurons / Q000166:cytology*; D009687:Nuclear Proteins / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex