Stxbp4 Regulates ΔNp63 Stability by Suppression of RACK1-Dependent Degradation
Stxbp4 Regulates ΔNp63 Stability by Suppression of RACK1-Dependent Degradation
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DOI：
10.1128/mcb.00449-09
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发表时间：
2009-07-01
影响因子：
5.3
通讯作者：
Prives, Carol
中科院分区：
文献类型：
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作者：
Li, Yingchun;Peart, Melissa J.;Prives, Carol
p63是p53肿瘤抑制家族的成员，对于表皮以及其它复层上皮的发育是必需的。集体证据表明，Delta Np 63蛋白，即p63的N-末端缺失版本，对于复层上皮细胞和鳞状细胞癌细胞的增殖和存活是必需的。但在DNA损伤的反应中，Delta Np 63蛋白部分通过蛋白质降解迅速下调。为了阐明Delta Np 63蛋白在增殖细胞中维持在相对高水平但在应激反应中不稳定的机制，我们试图鉴定调节p63稳定性的p63相互作用蛋白。我们发现Stxbp 4和RACK 1这两种支架蛋白在平衡Delta Np 63蛋白水平中起着核心作用。虽然Stxbp 4的功能是稳定Delta Np 63蛋白，但RACK 1靶向Delta Np 63进行降解。在正常生长条件下，Stxbp 4对于维持高基础水平的Delta Np 63和防止RACK 1介导的p63降解是必不可少的。然而，在遗传毒性应激后，Stxbp 4本身下调，与部分由RACK 1介导的Delta Np 63不稳定相关。总之，我们已经描绘了调节Delta Np 63蛋白在体内稳定性的关键机制。
p63, a member of the p53 tumor suppressor family, is essential for the development of epidermis as well as other stratified epithelia. Collective evidence indicates that Delta Np63 proteins, the N-terminally deleted versions of p63, are essential for the proliferation and survival of stratified epithelial cells and squamous cell carcinoma cells. But in response to DNA damage, Delta Np63 proteins are quickly downregulated in part through protein degradation. To elucidate the mechanisms by which Delta Np63 proteins are maintained at relatively high levels in proliferating cells but destabilized in response to stress, we sought to identify p63 interactive proteins that regulate p63 stability. We found that Stxbp4 and RACK1, two scaffold proteins, play central roles in balancing Delta Np63 protein levels. While Stxbp4 functions to stabilize Delta Np63 proteins, RACK1 targets Delta Np63 for degradation. Under normal growth conditions, Stxbp4 is indispensable for maintaining high basal levels of Delta Np63 and preventing RACK1-mediated p63 degradation. Upon genotoxic stress, however, Stxbp4 itself is downregulated, correlating with Delta Np63 destabilization mediated in part by RACK1. Taken together, we have delineated key mechanisms that regulate Delta Np63 protein stability in vivo.