Ultraviolet radiation induces phosphorylation and ubiquitin-mediated degradation of DeltaNp63alpha.
Ultraviolet radiation induces phosphorylation and ubiquitin-mediated degradation of DeltaNp63alpha.
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发表时间：
2005
期刊：
影响因子：
4.3
通讯作者：
M. Westfall;Amanda S. Joyner;C. Barbieri;M. Livingstone;J. Pietenpol
中科院分区：
文献类型：
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作者：
M. Westfall;Amanda S. Joyner;C. Barbieri;M. Livingstone;J. Pietenpol
DeltaNp63alpha是肿瘤抑制因子p53的同源物，作为一种转录抑制因子，对p53具有显性负作用。此外，DeltaNp63alpha在许多鳞状细胞癌中过表达，表明其在肿瘤发生中具有潜在作用。然而，调控p63的机制尚未阐明。本研究的目的是确定各种基因毒性应激对正常和转化鳞状上皮细胞中DeltaNp63alpha翻译后修饰和稳定性的影响。我们发现，在紫外线照射和紫杉醇处理后，正常细胞和转化细胞的DeltaNp63alpha蛋白水平均下降。紫外线和紫杉醇处理后，DeltaNp63alpha磷酸化被显著调节。此外，在对照组和紫外线处理的细胞中，DeltaNp63alpha蛋白水平以蛋白酶体依赖的方式调节，在紫外线处理或蛋白酶体抑制后，DeltaNp63alpha泛素化增加。我们的研究提供了DeltaNp63alpha在正常细胞增殖过程中的调控机制，特别是在应激后。此外，通过对蛋白酶体介导的降解的反向调控，细胞应激后p53和DeltaNp63alpha蛋白水平的反向调控可能允许特定靶基因的快速转录变化，这与这些家族成员在肿瘤抑制和细胞生长中的作用是一致的。
DeltaNp63alpha, a homologue of the tumor suppressor p53, acts as a transcriptional repressor with dominant negative effects towards p53. Additionally, DeltaNp63alpha is overexpressed in a number of squamous cell carcinomas, suggesting a potential role in oncogenesis. However, the mechanisms regulating p63 have yet to be elucidated. The goal of the current study was to determine the effect of various genotoxic stresses on DeltaNp63alpha posttranslational modification and stability in normal and transformed squamous epithelial cells. We found that DeltaNp63alpha protein levels decreased after ultraviolet radiation and paclitaxel treatment of both normal and transformed cells. After UV and paclitaxel treatment, DeltaNp63alpha phosphorylation was significantly modulated. Additionally, DeltaNp63alpha protein levels were regulated in a proteasome-dependent manner in control and UV treated cells with increased DeltaNp63alpha ubiquitination after UV treatment or proteasome inhibition. Our studies provide insight to a mechanism for DeltaNp63alpha regulation during normal cell proliferation and, in particular, after stress. Further, the inverse regulation of p53 and DeltaNp63alpha protein levels after cell stress through opposing regulation of proteasome-mediated degradation may allow for rapid transcriptional changes of specific target genes that are consistent with the roles of these family members in tumor suppression and cell growth.