Prenatal p25-activated Cdk5 induces pituitary tumorigenesis through MCM2 phosphorylation-mediated cell proliferation
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.
Authors
- Yongyan Ren
- Yue Pan (ORCID: https://orcid.org/0000-0002-3865-8583)
- Yao‐Wei Huang (ORCID: https://orcid.org/0000-0001-9755-8411)
- Yu-Ping Peng (ORCID: https://orcid.org/0000-0002-5966-0922)
- Hailiang Hu (ORCID: https://orcid.org/0000-0001-9205-1603)
- Yanlin Yu
- Wei Huang (ORCID: https://orcid.org/0000-0001-8279-6345)
- Hong Wu (ORCID: https://orcid.org/0000-0002-4939-5264)
- Yating Feng (ORCID: https://orcid.org/0000-0002-4523-4551)
- Weiwei Zhou (ORCID: https://orcid.org/0000-0003-1641-8965)
- Qi‐Qi Wang (ORCID: https://orcid.org/0000-0002-6588-8763)
- Guanchuan Lin (ORCID: https://orcid.org/0000-0002-9112-0280)
- Yingwei Huang
- Yihua Huang (ORCID: https://orcid.org/0000-0003-1890-0296)
- Lijuan Liu (ORCID: https://orcid.org/0000-0003-1138-5543)
- Zirui Chen (ORCID: https://orcid.org/0009-0000-0921-007X)
- Wei Li (ORCID: https://orcid.org/0000-0002-1732-8999)
- Xinghua Pan (ORCID: https://orcid.org/0000-0002-4277-2100)
- Yulong Zhang (ORCID: https://orcid.org/0000-0002-9855-5471)
- Kaibiao Xu (ORCID: https://orcid.org/0009-0009-5828-8004)
- Yawei Jiang
- Suyue Pan
- Kai He
- Yafang Hu
Institutions
- National Institutes of Health (US)
- Southern University of Science and Technology (CN)
- Nanfang Hospital (CN)
- National Cancer Institute (US)
- Southern Medical University (CN)
Publication Details
- Journal
- Neoplasia
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1016/j.neo.2024.101054
- Citations
- 4
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.94