多巴胺受体激动剂（DA）为垂体泌乳素瘤的首选治疗。我们以往研究表明，肿瘤细胞表面多巴胺2型受体（DRD2）的表达决定DA治疗效果，但是DRD2蛋白的降解机制不详。我们前期研究阐明，DRD2存在泛素化降解；通过酵母双杂交系统筛选其候选的泛素连接酶E3为KBTBD7；KBTBD7与DRD2直接结合并存在泛素化关系。因此我们提出设想：KBTBD7作为DRD2的泛素连接酶E3，调控其蛋白表达，从而改变肿瘤细胞对DA治疗的敏感性。为进一步证实上述想法，本课题将通过co-IP等技术确定泛素化位点；通过体外、原代肿瘤细胞及构建KBTBD7-/-小鼠等证明KBTBD7参与调节泌乳素瘤的药物敏感性；通过临床肿瘤大样本分析KBTBD7表达与患者药敏预后的相关性。该课题是我们以往研究的延续，将从DRD2蛋白的泛素化调控这一全新的角度阐释泌乳素腺瘤耐药的机制；而KBTBD7有望作为判定泌乳素瘤药敏的生物学标记。

Dopamine receptor agonists (DAs) are the first-line choice in treatment of prolactinomas. Our previous studies have shown that the expression of dopamine 2 receptor (DRD2) on the surface of tumor cells determines the efficacy of DA treatment, and that low DRD2 expression is correlated with DA resistance. However, the key mechanism of DRD2 protein degradation is unknown. Our recent studies have uncovered that 1) there was ubiquitin degradation of DRD2 protein; 2) The candidate ubiquitin ligase E3 was selected as KBTBD7 through two-hybrid system of per-yeast; 3) KBTBD7 directly interacts with, and ubiquitinates DRD2. Overexpression of KBTBD7 decreased the efficacy of DAs treatment. Therefore, we put forward our hypothesis that KBTBD7, as the ubiquitin ligase E3 of DRD2, regulates DRD2 protein expression and thus changes the sensitivity of tumor cells to DA treatment. In order to further confirm the above hypothesis, we need to investigate: (1) Protein immunoprecipitation and mass spectrometry experiments were used to identify ubiquitination sites of DRD2; (2) Through in vitro cell experiment, primary pituitary tumor cells, and construction of KBTBD7-/- mice, KBTBD7 should be further confirmed to be involved in regulating DRD2 expression and DAs sensitivity of prolactinoma cells; (3) The prognostic correlation between KBTBD7 expression and drug sensitivity will be analyzed by large clinical tumor samples. This study is a continuation of our previous researches, and we will elucidate a novel mechanism of drug resistance of prolactinomas from the perspective of the DRD2 protein ubiquitination regulation. If successful, KBTBD7 is expected to be a biomarker to determine the sensitivity of prolactinomas to DAs therapy.