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

Neoplasia. 2024 Nov:57:101054. doi: 10.1016/j.neo.2024.101054. Epub 2024 Oct 3.

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.

Keywords: Cdk5; Mcm2; Pituitary adenoma; Single-cell sequencing; p25.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenoma / metabolism
  • Adenoma / pathology
  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Cell Proliferation*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cyclin-Dependent Kinase 5* / genetics
  • Cyclin-Dependent Kinase 5* / metabolism
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Minichromosome Maintenance Complex Component 2* / genetics
  • Minichromosome Maintenance Complex Component 2* / metabolism
  • Phosphorylation
  • Pituitary Neoplasms* / genetics
  • Pituitary Neoplasms* / metabolism
  • Pituitary Neoplasms* / pathology

Substances

  • Minichromosome Maintenance Complex Component 2
  • Cyclin-Dependent Kinase 5