Gadd45a contributes to p53 stabilization in response to DNA damage
Gadd45a contributes to p53 stabilization in response to DNA damage
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DOI：
10.1038/sj.onc.1206907
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发表时间：
2003-11-20
期刊：
影响因子：
8
通讯作者：
Zhan, QM
中科院分区：
文献类型：
--
作者：
Jin, SQ;Mazzacurati, L;Zhan, QM
p53是细胞对DNA损伤应答的重要分子。在遗传毒性胁迫后，p53蛋白短暂稳定并在细胞核中积累，在那里它作为转录因子发挥作用并上调多个下游靶向基因，包括p21（Waf 1/Cip 1），Gadd 45 a和Bax。然而，p53稳定性的调节是复杂的，并且可能主要涉及p53的翻译后修饰，例如磷酸化和乙酰化。使用小鼠胚胎成纤维细胞（MEFs）来自Gadd 45 a基因敲除，我们发现，Gadd 45 a的破坏大大废除p53蛋白的稳定UVB治疗后。在Gadd 45 a-/- MEFs中，p53在Ser-15处的磷酸化显著降低。此外，UVB诱导的p53在p38激酶抑制剂的存在下被大大废除，但不是c-Jun N-末端激酶（JNK）和细胞外信号调节激酶（ERK），这表明p38蛋白激酶参与了p53诱导的调节。沿着上述发现，在细胞暴露于UVB后，Gadd 45 a的诱导型表达增强了p53的积累。综上所述，目前的研究表明，Gadd 45 a，一个传统的下游基因的p53，可能发挥作用的上游效应在p53稳定后的DNA损伤，从而定义了一个积极的反馈信号的p53通路的激活。
p53 is an important molecule in cellular response to DNA damage. After genotoxic stress, p53 protein stabilizes transiently and accumulates in the nucleus, where it functions as a transcription factor and upregulates multiple downstream-targeted genes, including p21(Waf1/Cip1), Gadd45a and Bax. However, regulation of p53 stabilization is complex and may mainly involve post-translational modification of p53, such as phosphorylation and acetylation. Using mouse embryonic fibroblasts (MEFs) derived from Gadd45a knockouts, we found that disruption of Gadd45a greatly abolished p53 protein stabilization following UVB treatment. Phosphorylation of p53 at Ser-15 was substantially reduced in Gadd45a-/- MEFs. In addition, p53 induction by UVB was shown to be greatly abrogated in the presence of p38 kinase inhibitor, but not c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK), suggesting that p38 protein kinase is involved in the regulation of p53 induction. Along with the findings presented above, inducible expression of Gadd45a enhanced p53 accumulation after cell exposure to UVB. Taken together, the current study demonstrates that Gadd45a, a conventional downstream gene of p53, may play a role as an upstream effector in p53 stabilization following DNA damage, and thus has defined a positive feedback signal in the activation of the p53 pathway.