Protein kinase C delta regulates Ser46 phosphorylation of p53 tumor suppressor in the apoptotic response to DNA damage.
Protein kinase C delta regulates Ser46 phosphorylation of p53 tumor suppressor in the apoptotic response to DNA damage.
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发表时间：
2006
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通讯作者：
K. Yoshida;Hanshao Liu;Y. Miki
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作者：
K. Yoshida;Hanshao Liu;Y. Miki
p53肿瘤抑制因子在细胞对基因毒性应激的反应中被激活。p53靶基因的转激活决定细胞周期阻滞和DNA修复或诱导凋亡；然而，负责这些不同功能的分子机制仍不清楚。最近的研究表明，p53在Ser（46）上的磷酸化与诱导p53AIP1的表达有关，从而导致细胞命运进入凋亡细胞死亡。此外，暴露于基因毒性应激后，p53DINP1表达并募集到p53的激酶，特异性磷酸化Ser（46）。在这里，我们发现促凋亡激酶，蛋白激酶C δ (pkcδ)，参与了p53在丝氨酸上的磷酸化（46）。PKCdelta介导的磷酸化是PKCdelta与p53相互作用所必需的。结果还表明，p53DINP1在暴露于遗传毒性物质时与PKCdelta结合。与这些结果一致，PKCdelta通过Ser（46）磷酸化增强p53依赖性细胞凋亡，以响应基因毒性应激。这些发现表明，在细胞对DNA损伤的反应中，PKCdelta调节p53诱导凋亡细胞死亡。
The p53 tumor suppressor is activated in the cellular response to genotoxic stress. Transactivation of p53 target genes dictates cell cycle arrest and DNA repair or induction of apoptosis; however, a molecular mechanism responsible for these distinct functions remains unclear. Recent studies revealed that phosphorylation of p53 on Ser(46) was associated with induction of p53AIP1 expression, resulting in the commitment of the cell fate into apoptotic cell death. Moreover, upon exposure to genotoxic stress, p53DINP1 was expressed and recruited a kinase(s) to p53 that specifically phosphorylated Ser(46). Here, we show that the pro-apoptotic kinase, protein kinase C delta (PKCdelta), is involved in phosphorylation of p53 on Ser(46). PKCdelta-mediated phosphorylation is required for the interaction of PKCdelta with p53. The results also demonstrate that p53DINP1 associates with PKCdelta upon exposure to genotoxic agents. Consistent with these results, PKCdelta potentiates p53-dependent apoptosis by Ser(46) phosphorylation in response to genotoxic stress. These findings indicate that PKCdelta regulates p53 to induce apoptotic cell death in the cellular response to DNA damage.