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J. Biol. Chem., Vol. 276, Issue 42, 39115-39122, October 19, 2001

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Osmotic Shock Induces G₁ Arrest through p53 Phosphorylation at Ser³³ by Activated p38^MAPK without Phosphorylation at Ser¹⁵ and Ser^20*

Hiroto Kishi^§, Kazumi Nakagawa, Mitsuhiro Matsumoto^§, Moritaka Suga^§, Masayuki Ando^§, Yoichi Taya^¶, and Masaru Yamaizumi

From the  Institute of Molecular Embryology and Genetics, Kumamoto University, Kuhonji 4-24-1, Kumamoto 862-0976, the ^§ First Department of Internal Medicine, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto 860-0811, and the ^¶ Radiobiology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan

Osmotic shock induced transient stabilization of p53, possibly due to increased degradation of Mdm2. Stabilized p53 was activated by p38^MAPK, resulting in G₁ arrest through induction of p21^WAF1. Among the postulated phosphorylation sites involved in p53 stabilization or activation (Ser¹⁵, Ser²⁰, Ser³³, and Ser⁴⁶), only Ser³³ was phosphorylated. Furthermore, interaction of p53 with the transcriptional coactivator p300 was induced, and Lys³⁸² of p53 was acetylated. Although inhibition of p38^MAPK did not prevent nuclear accumulation of p53, phosphorylation of Ser³³ was markedly suppressed by SB203580, a specific inhibitor of p38^MAPK. Under these conditions, acetylation of Lys³⁸² and induction of p21^WAF1 were also inhibited, and cells with elevated levels of p53 showed normal cell cycle progression. Activated p38^MAPK phosphorylated endogenous p53 at Ser³³ in living cells. In stable transformants expressing dominant negative MKK6, an upstream protein kinase of p38^MAPK, p53 stabilization was induced normally following osmotic shock, but phosphorylation of Ser³³, acetylation of Lys³⁸², and induction of p21^WAF1 were almost completely inhibited. These results suggest that phosphorylation at Ser³³ by p38^MAPK is critical for activation of p53 following osmotic shock. Phosphorylation of neither Ser¹⁵ nor Ser²⁰ was needed in this activation.

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