TRIM21介导4EBP1泛素化调控泌乳素细胞腺瘤药敏的作用及机制研究

垂体泌乳素细胞腺瘤首选药物卡麦角林（CAB）治疗，但10-20%的患者发生耐药，其机制不详。我们前期研究发现，CAB能抑制mTORC1底物4EBP1的磷酸化，从而抑制垂体肿瘤的生长。进一步研究发现，CAB也能够抑制4EBP1的泛素化，并找到其泛素连接酶TRIM21；TRIM21过表达增加泌乳素细胞腺瘤对CAB的耐药。据此，我们猜想：TRIM21介导4EBP1泛素化增强4EBP1磷酸化，降低CAB对4EBP1磷酸化的抑制，从而增强泌乳素细胞腺瘤的耐药。为进一步证实上述想法，该项目将深入研究：①TRIM21调控4EBP1泛素化的机制；②4EBP1泛素化对其磷酸化及泌乳素细胞腺瘤药敏的影响；③TRIM21对泌乳素细胞腺瘤药敏的影响及是否为药敏标记物。该课题将从TRIM21对4EBP1蛋白的泛素化调控这一全新的角度来阐释泌乳素细胞腺瘤耐药的新机制，有望发现全新治疗靶点和生物标记物。

Dopamine agonists (DAs), such as cabergoline (CAB), are the first-line treatments for prolactinomas. However,10-20% of prolactinomas are resistant to DA treatment, and the mechanism is unknown. Our previous studies found that CAB can inhibit the phosphorylation of the mTORC1 substrate 4EBP1, thereby inhibiting the growth of pituitary tumors. We subsequently found that CAB can inhibit the ubiquitination of 4EBP1 and find out the ubiquitin-ligase enzyme TRIM21 for 4EBP1; TRIM21 overexpression increases the resistance of prolactinoma cells to CAB. Based on this, we hypothesize that TRIM21 not only mediates 4EBP1 ubiquitination but also enhances the phosphorylation of 4EBP1 and reduces the inhibition of CAB on the phosphorylation of 4EBP1， increasing the resistance of prolactinoma cells to drug treatment. To further confirm the above ideas, the project will delve into the following:①The mechanism of TRIM21 regulating 4EBP1 ubiquitination; ②The effect of the ubiquitinated 4EBP1 on its phosphorylation and the drug sensitivity of prolactinomas; ③The role of TRIM21 on drug sensitivity of prolactinomas and whether it is a drug sensitivity marker. We will elucidate a novel mechanism of drug resistance of prolactinomas from a new perspective of the ubiquitination regulation of 4EBP1 protein by TRIM21, and it is expected to discover new therapeutic targets and biomarkers.