A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73
A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73
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DOI：
10.1101/gad.319905
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发表时间：
2005-02-01
影响因子：
10.5
通讯作者：
Shaul, Y
中科院分区：
文献类型：
--
作者：
Asher, G;Tsvetkov, P;Shaul, Y
蛋白质降解是一个重要的和高度调控的过程。肿瘤抑制因子p53和p73的蛋白酶体降解受多聚泛素化和不依赖于泛素的过程的调节。在这里，我们表明，这一不依赖于泛素的过程是由20 S蛋白酶体介导的，并受到NQO1的调节。NQO1以NADH依赖性方式与p53和p73物理相互作用，并保护它们免受20S蛋白酶体降解。值得注意的是，细胞中绝大多数NQO1与20 S蛋白酶体物理相关，表明NQO1作为20 S蛋白酶体的看门人发挥作用。我们进一步表明，这一途径在电离辐射引起的p53积累中起着重要作用。我们的研究结果提供了第一个证据，在体内降解p53和p73的20 S蛋白酶体和NQO1和NADH水平的调节。
Protein degradation is an essential and highly regulated process. The proteasomal degradation of the tumor suppressors p53 and p73 is regulated by both polyubiquitination and by an ubiquitin-independent process. Here, we show that this ubiquitin-independent process is mediated by the 20S proteasomes and is regulated by NQO1. NQO1 physically interacts with p53 and p73 in an NADH-dependent manner and protects them from 20S proteasomal degradation. Remarkably, the vast majority of NQO1 in cells is found in physical association with the 20S proteasomes, suggesting that NQO1 functions as a gatekeeper of the 20S proteasomes. We further show that this pathway plays a role in p53 accumulation in response to ionizing radiation. Our findings provide the first evidence for in vivo degradation of p53 and p73 by the 20S proteasomes and its regulation by NQO1 and NADH level.