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

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

Neoplasia: An International Journal for Oncology Research (Nov 2024)

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

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

Affiliations

Yingwei Huang: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Neurology, Jiangmen Central Hospital, Jiangmen, China
Qiqi Wang: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Neurology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
Weiwei Zhou: Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Yawei Jiang: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Kai He: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
Wei Huang: Department of Neurology, the First People's Hospital of Shunde, Southern Medical University, Guangzhou, China
Yating Feng: Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Hong Wu: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Lijuan Liu: Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Yue Pan: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Yihua Huang: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Zirui Chen: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Wei Li: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Yaowei Huang: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guanchuan Lin: Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Yulong Zhang: Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Yongyan Ren: Central Laboratory, Southern Medical University, Guangzhou, China
Kaibiao Xu: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Yanlin Yu: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Yuping Peng: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
Xinghua Pan: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China; Precision Regenerative Medicine Research Centre, Medical Science Division, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China; China Ministry Education Key Laboratory of Infectious Diseases Research in South China, Southern Medical University, Guangzhou, China; Co-corresponding author.
Suyue Pan: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Co-corresponding author.
Hailiang Hu: Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China; Co-corresponding author.
Yafang Hu: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Corresponding author at: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China

Journal volume & issue: Vol. 57
p. 101054

Abstract

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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.

Published in Neoplasia: An International Journal for Oncology Research

ISSN: 1522-8002 (Print); 1476-5586 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.journals.elsevier.com/neoplasia/

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