Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, 79104 Freiburg, Germany.
Mol Cell. 2011 Jun 10;42(5):584-96. doi: 10.1016/j.molcel.2011.03.033.
Activation of p53 by DNA damage results in either cell-cycle arrest, allowing DNA repair and cell survival, or induction of apoptosis. As these opposite outcomes are both mediated by p53 stabilization, additional mechanisms to determine this decision must exist. Here, we show that glycogen synthase kinase-3 (GSK-3) is required for the p53-mediated induction of the proapoptotic BH3 only-protein PUMA, an essential mediator of p53-induced apoptosis. Inhibition of GSK-3 protected from cell death induced by DNA damage and promoted increased long-term cell survival. We demonstrate that GSK-3 phosphorylates serine 86 of the p53-acetyltransferase Tip60. A Tip60(S86A) mutant was less active to induce p53 K120 acetylation, histone 4 acetylation, and expression of PUMA. Our data suggest that GSK-3 mediated Tip60S86 phosphorylation provides a link between PI3K signaling and the choice for or against apoptosis induction by p53.
DNA 损伤激活 p53 后，会导致细胞周期停滞，从而允许进行 DNA 修复和细胞存活，或诱导细胞凋亡。由于这两种相反的结果都是通过 p53 稳定介导的，因此必然存在其他决定这种结果的机制。在这里，我们发现糖原合酶激酶-3（GSK-3）对于 p53 介导的促凋亡 BH3 仅有蛋白 PUMA 的诱导是必需的，PUMA 是 p53 诱导细胞凋亡的重要介质。抑制 GSK-3 可防止由 DNA 损伤引起的细胞死亡，并促进长期细胞存活。我们证明 GSK-3 磷酸化 p53-乙酰转移酶 Tip60 的丝氨酸 86 位。Tip60（S86A）突变体在诱导 p53 K120 乙酰化、组蛋白 4 乙酰化和 PUMA 表达方面的活性降低。我们的数据表明，GSK-3 介导的 Tip60S86 磷酸化提供了 PI3K 信号和 p53 诱导细胞凋亡的选择之间的联系。
