AP2alpha alters the transcriptional activity and stability of p53.
AP2alpha alters the transcriptional activity and stability of p53.
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发表时间：
2006
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影响因子：
8
通讯作者：
P. Stabach;M. Thiyagarajan;G. Woodfield;R. Weigel
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文献类型：
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作者：
P. Stabach;M. Thiyagarajan;G. Woodfield;R. Weigel
AP 2 α和p53形成核复合物，建立功能伙伴关系，调节参与细胞生长和转移的某些基因的表达。AP 2 α的生长效应通过p21 WAF 1/CIP 1介导，AP 2 α共激活p21的能力需要p53。在此，我们已经将p53的AP 2结合区定位于氨基酸305-375。对26个不同的p53等位基因的分析建立了AP 2 α结合和转录共激活之间的相关性。L350 P点突变是唯一的非结合等位基因，保留正常的转录活性的报告分析。虽然野生型和L350 P等位基因促进AP 2 α与p21启动子的结合，但L350 P等位基因诱导内源性p21基因的能力显著降低，表明与内源性p53靶基因激活的报告基因测定相比，活性存在显著差异。有趣的是，在辐射抑制p53介导的诱导p21的情况下，AP 2的表达，这种效果是由AP 2 α过表达诱导的p53稳定性降低解释。我们的结论是，AP 2 α通过共激活和稳定性降低对p53活性具有竞争性影响。这些发现可能提供了一种机制来解释肿瘤组织中AP 2和p21表达之间相关性的差异。
AP2alpha and p53 form nuclear complexes that establish a functional partnership, which regulates the expression of certain genes involved in cell growth and metastasis. The growth effects of AP2alpha are mediated through p21WAF1/CIP1 and the ability for AP2alpha to coactivate p21 requires p53. Herein, we have localized the AP2-binding region of p53 to amino acids 305-375. Analysis of 26 distinct p53 alleles established a correlation between AP2alpha binding and transcriptional coactivation. The L350P point mutation was the only nonbinding allele that retained normal transcriptional activity by reporter assay. Although both wild-type and L350P alleles facilitated binding of AP2alpha to the p21 promoter, the L350P allele was significantly reduced in its ability to induce the endogenous p21 gene, demonstrating a striking difference in activity comparing reporter assays with activation of endogenous p53 target genes. Interestingly, expression of AP2 in the absence of radiation repressed p53-mediated induction of p21 and this effect was explained by a reduction in p53 stability induced by AP2alpha overexpression. We conclude that AP2alpha has competing effects on p53 activity through coactivation and decreased stability. These findings may provide a mechanism to account for the discrepancies reported for the association between AP2 and p21 expression in tumor tissue.