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

in Neoplasia (New York, N.Y.) by Yingwei Huang, Qiqi Wang, Weiwei Zhou, Yawei Jiang, Kai He, Wei Huang, Yating Feng, Hong Wu, Lijuan Liu, Yue Pan, Yihua Huang, Zirui Chen, Wei Li, Yaowei Huang, Guanchuan Lin, Yulong Zhang, Yongyan Ren, Kaibiao Xu, Yanlin Yu, Yuping Peng, Xinghua Pan, Suyue Pan, Hailiang Hu, Yafang Hu

TLDR

  • The study investigates how a protein called cyclin-dependent kinase 5 (Cdk5) affects the growth of tumors in the pituitary gland. The study used a mouse model to observe that Cdk5 helps a protein called minichromosome maintenance protein 2 (Mcm2) to grow and divide, which leads to the growth of tumors in the pituitary gland. The study also found that Cdk5 helps another protein called Mcm2 to grow and divide, which also leads to the growth of tumors in the pituitary gland. The study also found that silencing Cdk5 or Mcm2 can stop the growth of these tumors. The study provides important information about how Cdk5 and Mcm2 work together to cause tumors in the pituitary gland.

Abstract

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.

Overview

  • The study investigates the role of cyclin-dependent kinase 5 (Cdk5) in pituitary adenoma tumorigenesis. The study uses a mouse model with CaMKII promoter-driven transgenic induction of p25 to observe intermediate lobe-originated pituitary adenoma producing non-functional proopiomelanocortin (POMC)-derived peptides under persistent p25 overexpression. Single-cell RNA sequencing reveals 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. The primary objective of the study is to understand the role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis and to identify potential therapeutic targets for the treatment of pituitary adenomas.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study found that prenatal p25-activated Cdk5 phosphorylates minichromosome maintenance protein 2 (Mcm2), enhancing minichromosome maintenance (MCM) family proteins and driving intermediate lobe-originated melanotrope-originated pituitary tumorigenesis. In a mouse model with CaMKII promoter-driven transgenic induction of p25, the study 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. The key findings of the study are that prenatal p25-activated Cdk5 phosphorylates Mcm2, enhancing minichromosome maintenance (MCM) family proteins and driving intermediate lobe-originated melanotrope-originated pituitary tumorigenesis. The study also identified Mcm2 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.

Implications and Future Directions

  • The study's findings have significant implications for the field of research or clinical practice. The study provides a new mouse model of intermediate lobe-originated pituitary adenoma induced by p25/Cdk5 and unveils a previously unappreciated role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis. The study also identifies Mcm2 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. Future research directions could include further investigation of the role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis, exploring the potential of Cdk5 and Mcm2 as therapeutic targets for the treatment of pituitary adenomas, and identifying other potential phosphorylated substrates of Cdk5 in pituitary adenoma tumorigenesis.
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