Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Neurology, Jiangmen Central Hospital, Jiangmen, China.
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Neurology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
Neoplasia. 2024 Nov;57:101054. doi: 10.1016/j.neo.2024.101054. Epub 2024 Oct 3.
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.
周期蛋白依赖性激酶 5（Cdk5）的异常表达已在垂体腺瘤中报道。然而，Cdk5 在肿瘤发生中的作用尚不清楚。我们表明，产前 p25 激活的 Cdk5 使微小染色体维持蛋白 2（Mcm2）磷酸化，增强微小染色体维持（MCM）家族蛋白并驱动位于中间叶的黑素细胞起源的垂体肿瘤发生。在 CaMKII 启动子驱动的 p25 转基因诱导的小鼠模型中，我们观察到中间叶起源的垂体腺瘤在持续的 p25 过表达下产生无功能的 proopiomelanocortin（POMC）衍生肽。单细胞 RNA 测序显示 Mcm2 在肿瘤进展中可能发挥重要作用。随后，Mcm2 被鉴定为 Cdk5 的潜在磷酸化底物，介导黑素细胞的肿瘤性增殖。沉默 Cdk5 或 Mcm2 抑制了 293T 细胞系中的细胞增殖和集落形成。因此，我们的研究结果提供了一种由 p25/Cdk5 诱导的中间叶起源的垂体腺瘤的新小鼠模型，并揭示了 Cdk5 和 Mcm2 在垂体腺瘤发生中的以前未被认识的作用。
