RACK1 and stratifin target DeltaNp63alpha for a proteasome degradation in head and neck squamous cell carcinoma cells upon DNA damage.
RACK1 and stratifin target DeltaNp63alpha for a proteasome degradation in head and neck squamous cell carcinoma cells upon DNA damage.
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发表时间：
2004
期刊：
影响因子：
4.3
通讯作者：
A. Fomenkov;R. Zangen;Yiping Huang;M. Osada;Zhongmin Guo;Tanya Fomenkov;B. Trink;D. Sidransky;E. Ratovitski
中科院分区：
文献类型：
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作者：
A. Fomenkov;R. Zangen;Yiping Huang;M. Osada;Zhongmin Guo;Tanya Fomenkov;B. Trink;D. Sidransky;E. Ratovitski
具有反式激活(TA)结构域的P53家族成员可诱导细胞周期停滞并促进细胞凋亡。然而，缺乏TA结构域的DeltaNp63亚型在体外和vGammavo中促进细胞增殖和肿瘤形成。虽然P53、TAp63或TAp73在DNA损伤后是稳定的，但我们发现遗传毒性应激剂诱导了鳞状细胞癌细胞中DeltaNp63α的急剧减少和磷酸化。进一步的研究表明，RACK1通过其WD40结构域与p63αC-末端结构域物理结合。然而，顺铂作用下，层翅素与磷酸化的DeltaNp63pha结合。在顺铂诱导的DNA损伤后，层翅介导DeltaNp63α的核输出进入细胞质，然后RACK1靶向后者进入蛋白酶体降解途径，可能是E3泛素连接酶。此外，Strayfin和RACK1的siRNA敲除分别抑制了DeltaNp63α的核输出和蛋白质降解。我们的数据表明，DeltaNp63α的修饰和下调是人头颈部癌症细胞对DNA损伤反应的主要决定因素之一。
p53 family members with a transactivation (TA) domain induce cell cycle arrest and promote apoptosis. However, DeltaNp63 isotypes lacking the TA-domain promote cell proliferation and tumorigenesis in vitro and in vgammavo. Although p53, TAp63 or TAp73 are stabilized upon DNA damage, we found that the genotoxic stress agents induced a dramatic decrease and phosphorylation of DeltaNp63alpha in squamous cell carcinoma cells. Further work revealed that RACK1 physically associated with the p63alpha C-terminal domain through its WD40 domain. However, stratifin binds with phosphorylated DeltaNp63alpha in response to cisplatin. Upon DNA damage induced by cisplatin, stratifin mediated a nuclear export of DeltaNp63alpha into cytoplasm and then RACK1 targeted latter into a proteasome degradation pathway possibly serving as an E3 ubiquitin ligase. Moreover, siRNA knockdown of both stratifin and RACK1 inhibited a nuclear export and protein degradation of DeltaNp63alpha, respectively. Our data suggest that modification and down regulation of DeltaNp63alpha is one of the major determinants of the cellular response to DNA damage in human head and neck cancers.