Role of SENP1 in Prostate Cancer Pathogenesis

描述（由申请人提供）：我们的实验室克隆了第一个人sentrin/SUMO特异性蛋白酶SENP 1。这种酶的异肽酶活性通过SUMO（小泛素样修饰物）使翻译后修饰去缀合。虽然其催化活性已被表征，但SENP 1的生物学意义仍然未知。最近，我们观察到SENP 1增强雄激素受体（AR）依赖性转录。许多报告得出结论，AR活性的增强促进前列腺癌（PCa）的发展，前列腺癌是男性中最常诊断的癌症。原位杂交研究表明SENP 1在癌前病变和癌病变中过表达，但在正常前列腺上皮中不表达。此外，SENP 1的稳定过表达促进PCa细胞生长和转化。目前，尚不清楚SENP 1的表达增强是否会促进前列腺癌的发生;因此，我们建议测试SENP 1的诱导是否会调节前列腺癌的发生和进展。使用诱导系统，将探索SENP 1表达对LNCaP细胞增殖和裸鼠中肿瘤生长的影响。此外，将评估在前列腺中过表达SENP 1的转基因小鼠的肿瘤形成， 侵略性

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.