SCP1通过c-Myc去磷酸化调控肝癌发生的机制和功能研究

Oncoprotein c-Myc is frequently overexpressed in various tumors. It is well-established that phosphorylation of Myc at Serine 62(S62) is essential for its stability and function. Recently, we identified a novel protein phosphatase SCP1 which can specifically dephosphorylate c-Myc at S62. However， whether dephosphorylation of c-Myc is involved in the tumorigenesis is still unclear. Moreover, we found that SCP1 phosphatase activity is dramatically blocked by phosphorylation of Serine 245 (S245) . Our preliminary data indicated that the protein expression of c-Myc and SCP1 were negative correlation in 50% of liver cancer tissues, suggesting that dephosphorylation of c-Myc at S62 may regulate the c-Myc protein stability and function and consequently regulate the hepatocellular tumorigenesis. In addition, we found that SCP1 and c-Myc were highly expressed in some tissue samples. Thus, we hypothesize that phosphorylation of SCP1 at S245 may inhibit the phosphatase activity of SCP1 to dephosphorylate c-Myc..In this study, we plan to study that whether SCP1 negatively regulate the tumorigenesis of liver cancer using mouse model, and uncover the mechanism of phosphorylation SCP1 at S245. We will further study the mechanism by which phosphorylation of SCP1 at S245 and its relation with hepatocellular tumorigenesis. The study is important for understanding the mechanism of hepatocellular tumorigenesis.

c-Myc是一个重要的癌蛋白，其异常过表达与许多肿瘤的发生密切相关。已知c-Myc 62位丝氨酸（S62）的去磷酸化对于其蛋白稳定性和生物功能至关重要。磷酸酯酶SCP1是申请人新发现的能特异对c-Myc S62去磷酸化的一个磷酸酯酶。而且，发现SCP1的245丝氨酸(S245)被磷酸化后抑制了SCP1对c-Myc的去磷酸化。在此基础上, 申请人进一步发现c-Myc和SCP1在50%的肝癌样本中呈负相关，提示SCP1可能通过调控c-Myc的蛋白稳定性和生物活性参与调控肝癌的发生。另外，有些肝癌样品中SCP1和c-Myc同时高表达,这些结果提示在某些生理或病理状况下SCP1的S245可能被磷酸化而失去对c-Myc的去磷酸化。在本申请中我们拟研究SCP1对c-Myc的去磷酸化是否会影响肝癌的发生，以及SCP1的S245被磷酸化的分子机制;同时研究SCP1的S245被磷酸化后与肝癌发生发展关系。

癌蛋白c-Myc在许多癌症中经常被上调。 我们的研究结果表明，SCP1是一种新型磷酸酶，可使c-Myc Ser62去磷酸化，并负调节c-Myc稳定性，转录活性和细胞增殖。 保守的潜在磷酸化位点Ser245对SCP1磷酸酶活性至关重要。 模拟磷酸化的S245D突变体完全丧失了磷酸酶活性以及对细胞增殖的抑制活性。 我们的研究表明SCP1可能是癌症的潜在肿瘤抑制因子。