Role of SENP1 in Prostate Cancer Pathogenesis

描述(申请人提供)：本实验室克隆了第一个人类Sentrin/相扑专一性的蛋白酶SENP1。该酶的异肽酶活性与SUMO(小泛素样修饰物)的翻译后修饰相反。虽然SENP1的催化活性已被表征，但其生物学意义尚不清楚。最近，我们观察到SENP1增强雄激素受体(AR)依赖的转录。许多报道认为，AR活性的增强促进了前列腺癌(PCA)的发展，前列腺癌是男性最常见的癌症。原位杂交研究表明，SENP1在癌前病变和癌组织中过表达，但在正常前列腺上皮中不表达。此外，SENP1的稳定过表达促进了PCa细胞的生长和转化。目前，尚不清楚SENP1的表达增强是否促进前列腺癌的发生；因此，我们建议测试SENP1的诱导是否调节前列腺癌的发生和发展。利用诱导系统，探讨SENP1表达对LNCaP细胞增殖和裸鼠体内肿瘤生长的影响。此外，在前列腺中过度表达SENP1的转基因小鼠将被评估肿瘤形成和 咄咄逼人。

DESCRIPTION (provided by applicant): Our laboratory cloned the first human sentrin/SUMO-specific protease, SENP1. The isopeptidase activity of this enzyme deconjugates the posttranslation modification by SUMO (small ubiquitin-like modifier). Although its catalytic activity has been characterized, the biological significance of SENP1 remains unknown. Recently we observed that SENP1 enhances androgen receptor (AR)-dependent transcription. Numerous reports conclude that enhancement of AR activity promotes development of prostate cancer (PCa), the most frequently diagnosed carcinoma in males. In situ hybridization studies indicate an overexpression of SENP1 in pre-cancer and cancer lesions, but not normal prostate epithelia. Also, stable overexpression of SENP1 prompts PCa cell growth and transformation. Currently, it is unknown whether enhanced expression of SENP1 promotes prostate carcinogenesis; hence we propose to test whether induction of SENP1 regulates the development and progression of prostate cancer. Using an inducible system, the effect of SENP1 expression on proliferation of LNCaP cells and tumor growth in nude mice will be explored. Also, transgenic mice overexpressing SENP1 in the prostate will be evaluated for tumor formation and aggressiveness.