Ser46 phosphorylation of p53 is not always sufficient to induce apoptosis: multiple mechanisms of regulation of p53-dependent apoptosis.
The tumor suppressor gene p53 plays a central role in determining cell fate in response to DNA damage; cells may undergo either senescence or apoptosis, depending on cell type. Phosphorylation of Serine 46 (Ser(46)) of p53 is considered to be a primary determinant for the induction of apoptosis, by selectively inducing transactivation of p53 target genes that have proapoptotic function. However, the generality of this mechanism of regulation of p53 remains a matter of debate. We investigated the role of p53 phosphorylation in adriamycin (ADR)-induced apoptosis. We found that Ser(46) was phosphorylated in four different cell lines undergoing ADR-induced senescence, as well as in two different cell lines undergoing ADR-induced apoptosis. Using alanine and glutamic acid substitution mutants of p53 Ser(46), we showed that Ser(46 )phosphorylation is not a prerequisite for induction of the proapoptotic gene AIP1. These results indicate that Ser(46) phosphorylation of p53 is not required for ADR-induced apoptosis.
Kurihara
Akira
A
Center for Interdisciplinary Research, Tohoku University, Aramaki, 6-3 Aoba, Aoba-ku, Sendai, Japan 980-8578.
Nagoshi
Hirokazu
H
Yabuki
Masato
M
Okuyama
Ryuhei
R
Obinata
Masuo
M
Ikawa
Shuntaro
S
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012694:Serine; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases