摘要
在全球癌症发病率不断升高的今天,人们不断寻找肿瘤预防和治疗的手段。在过去几十年里,尽管在肿瘤研究中取得令人鼓舞的进展,肿瘤的预防和治疗却尚未完善。最近几年来,研究发现蛋白酶体抑制剂是一种有效而令人鼓舞的抗癌治疗手段。蛋白酶体是一种催化蛋白水解的复合体。而REGy是一种11S蛋白酶体激活因子,它的许多生物学功能目前还不清楚。实验证明,REGy/蛋白酶体能降解在乳腺癌中经常发生过表达的蛋白SRC-3,这提示REGy在肿瘤进展中具有调节作用。而且有实验证实p21为REGy/蛋白酶体的另一个靶目标,揭示了REGy可能在肿瘤形成各个阶段均起着重要作用。因此,进一步认识REGy/蛋白酶体将有助于发现新的肿瘤治疗方法。蛋白质翻译后修饰是细胞内蛋白质发挥生物学功能的重要调节机制之一。SUMO分子是一种泛素样分子,也参与蛋白质的翻译后修饰。与泛素化不同的是,SUMO化修饰并不介导靶蛋白的蛋白酶体降解,而是可逆性修饰靶蛋白。现已有多项研究表明,SUMO化修饰可以改变蛋白质的稳定性,并影响蛋白质的定位、功能以及蛋白质之间的相互作用。
我们研究发现REGy的SUMO化修饰在体内和体外均能发生。于是我们用多种专业软件对REGy氨基酸序列进行分析,并预测了多个潜在的SUMO化修饰位点。SUMO化修饰连接酶PIAS1与REGy有着相互作用,而且能够促进其SUMO化修饰。我们还发现REGy的SUMO化修饰发生在多个位点,包括K6,K14以及K12。通过对突变体的分析,我们发现这些SUMO化修饰位点同时影响着细胞内REGy的SUMO修饰。SUMO化修饰介导了REGy的亚细胞定位,并增加了这种蛋白酶体激活因子的稳定性。因为SUMO化修饰使得REGy与p21 Waf/Cipl之间的相互作用减弱,所以SUMO化修饰缺陷型REGy突变体表现出降解p21能力的下降。总体来说,我们发现了之前从未被报道的一种调节蛋白酶体激活因子REGy活性的机制。这种调节机制可能使REGy能够更为广泛的在蛋白质降解过程中起到作用。
We are constantly looking for the methods for cancer prevention and therapy when the cancer morbidities in the world are increasing. In the past decades, cancer research has made encouraging progress; but prevention and treatment of cancers have not been perfected. Recent years, proteasome inhibitors have been shown to be an exciting and effective treatment for cancers. Proteasome is a complex which can catalyze proteolysis. REGγis a 11s proteasome activator. The biological roles of REGγare yet to be explored. We previously demonstrated that REGγ/proteasome could degrade SRC-3 which is an oncogene frequently amplified and overexpressed in breast cancers. It's suggested that REGγcan regulate the process of tumor development. Moreover, we also found p21 is another target protein of REGγ/proteasome, which revealed REGγalso had a role in the regulation of the cell cycle through its ability to influence the level of a cell-cycle regulator(s). Thus further studies on REGγ/proteasome may lead to novel therapeutics for cancer. Posttranslational modifications are modifications that cells used to control the function of proteins. SUMO modification is one kind of posttranslational modification. SUMO is a small poly-peptide which is structurally related to ubiquitin. Unlike the situation with ubiquitination, SUMO modification does not appear to target proteins for proteasome-mediated degradation and it is a reversible process. A number of studies show that SUMO modification can alter the stability of the target protein and will also affect protein subcellular distribution, protein function, protein-protein interaction.
In our study we found that REGγcan be SUMOylated in vitro and in vivo. So we analyzed the amino acid sequence of REGγusing different professional software and predicted several sites as potential SUMOylation sites. The SUMO-E3 protein inhibitor of activated STAT (PIAS)1 physically associates with REGγand promotes SUMOylation of REGγ. SUMO modification of REGγwas found to occur at multiple sites, including K6, K14, and K12. Mutation analysis indicated that these SUMO sites simultaneously contributed to the SUMOylation status of REGγin cells. SUMO modification of REGγwas revealed to mediate subcellular distribution of REGγand also increased stability of this proteasome activator. SUMOylation-deficient REGγdisplayed attenuated ability to degrade p21Waf//Cip1 due to reduced affinity of the REGγSUMOylation-defective mutant for p21. Taken together, we report a previously unrecognized mechanism regulating the activity of the proteasome activator REGγ. This regulatory mechanism may enable REGγto function as a more potent factor in protein degradation with a broader substrate spectrum.
引文
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