Prenatal p25-activated Cdk5 induces pituitary tumorigenesis through MCM2 phosphorylation-mediated cell proliferation

• Published in: Neoplasia (New York, N.Y.) Vol. 57; p. 101054
• Main Authors: Huang, Yingwei, Wang, Qiqi, Zhou, Weiwei, Jiang, Yawei, He, Kai, Huang, Wei, Feng, Yating, Wu, Hong, Liu, Lijuan, Pan, Yue, Huang, Yihua, Chen, Zirui, Li, Wei, Huang, Yaowei, Lin, Guanchuan, Zhang, Yulong, Ren, Yongyan, Xu, Kaibiao, Yu, Yanlin, Peng, Yuping, Pan, Xinghua, Pan, Suyue, Hu, Hailiang, Hu, Yafang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024; Neoplasia Press; Elsevier
• Subjects: Cdk5; Mcm2; Original Research; p25; Pituitary adenoma; Single-cell sequencing; IHC; MRI; ACTH; CDK; PRL; WB; co-IP; siRNAs; scRNA-seq; KDR; CCK-8; KEGG; FSH; α-MSH; IF; tTA; H&E; MS; TSH; Single-cell sequencing; Bi-Tg; POMC; p25; Cdk5; MCM; Pituitary adenoma; LH; Mcm2; ELISA
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2024.101054

Aberrant expression of cyclin-dependent kinase 5 (Cdk5) has been reported in pituitary adenomas. However, the role of Cdk5 in the tumorigenesis remains unclear. We show that prenatal p25-activated Cdk5 phosphorylates minichromosome maintenance protein 2 (Mcm2), enhancing minichromosome maintenance (MCM) family proteins and driving intermediate lobe-located melanotrope-originated pituitary tumorigenesis. In a mouse model with CaMKII promoter-driven transgenic induction of p25, we observed intermediate lobe-originated pituitary adenoma producing non-functional proopiomelanocortin (POMC)-derived peptides under persistent p25 overexpression. Single-cell RNA sequencing revealed Mcm2 may play an important role during tumor progression. Subsequently, Mcm2 was identified as a potential phosphorylated substrate of Cdk5, mediating the tumorous proliferation of melanotrope cells. Silencing Cdk5 or Mcm2 suppressed cell proliferation and colony formation in the 293T cell lines. Therefore, our findings provide a new mouse model of intermediate lobe-originated pituitary adenoma induced by p25/Cdk5 and unveil a previously unappreciated role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis. Graphical abstract of Cdk5/p25 phosphorylation of Mcm2, promoting DNA replication and pituitary tumorigenesis in p25OE mice and human adenomas. [Display omitted]