转录因子Pit-1磷酸化及其调控机制在垂体瘤发生发展中的作用研究

垂体瘤是一种常见的神经系统肿瘤。垂体特异转录因子-1 (pituitary specific transcription factor，Pit-1)是垂体发育中最重要的组织特异性转录因子之一。前期生物信息学筛查发现Pit-1的126位丝氨酸是细胞周期素依赖激酶5（Cyclin dependent kinase 5，Cdk5）潜在的特异性磷酸化位点，且Cdk5和Pit-1存在相互作用。实验表明垂体瘤组织中Pit-1的Ser126位磷酸化水平明显高于正常垂体，提示Pit-1的126位磷酸化可能具有重要作用。本研究主要探讨Cdk5如何通过磷酸化Pit-1调控基因转录、激素合成等进程，以及Pit-1 126位丝氨酸磷酸化对转录复合物形成，转录活性调节及下游信号转导的影响，并通过组织芯片筛查Pit-1 126位磷酸化水平与垂体瘤激素分泌、耐药与预后的关系，期望为垂体瘤探寻新的分子靶点提供理论依据。

Pituitary adenomas are commonly encountered intracranial neoplasms. Pit-1 plays a key role in the specification, expansion and survival of three specific pituitary cell types (somatotropes, lactotropes and a subset of thyrotropes) during the development of the anterior pituitary. Based on sequence analysis, we identified Ser-126 in Pit-1 as the only consensus phosphorylation site for Cyclin dependent kinase 5 (Cdk5). We detected a physical interaction between Cdk5 and Pit-1 in pituitary adenomas. In the preliminary experiments indicated that inhibition of Cdk5 activity reduced the release of PRL and GH in GH3 cells. Pit-1 pSer-126 expression is significantly increased in human pituitary adenomas as compared to normal pituitary. In the current study, through further investigation the effect of phosphorylation of Pit-1 on Ser-126 on the function of transcription regulation, the formation of transcription complexes and its signal transduction pathway in pituitary adenomas, reveal CDK5-mediated Pit-1 phosphorylation controls prolactin and growth hormone pituitary adenomas progression and Pit-1 pSer-126 serves as a potential prognostic biomarker for molecular diagnosis and therapy of pituitary adenomas.