Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis

Karine Pozo, Antje Hillmann, Alexander Augustyn, Florian Plattner, Tao Hai, Tanvir Singh, Saleh Ramezani, Xiankai Sun, Roswitha Pfragner, John D. Minna, Gilbert J. Cote, Herbert Chen, James A. Bibb, Fiemu E. Nwariaku

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer of thyroid C-cells, for which few treatment options are available. We have recently reported a role for cyclin-dependent kinase 5 (CDK5) in MTC pathogenesis. We have generated a mouse model, in which MTC proliferation is induced upon conditional overexpression of the CDK5 activator, p25, in C-cells, and arrested by interrupting p25 overexpression. Here, we identify genes and proteins that are differentially expressed in proliferating versus arrested benign mouse MTC. We find that downstream target genes of the tumor suppressor, retinoblastoma protein, including genes encoding cell cycle regulators such as CDKs, cyclins and CDK inhibitors, are significantly upregulated in malignant mouse tumors in a CDK5-dependent manner. Reducing CDK5 activity in human MTC cells down-regulated these cell cycle regulators suggesting that CDK5 activity is critical for cell cycle progression and MTC proliferation. Finally, the same set of cell cycle proteins was consistently overexpressed in human sporadic MTC but not in hereditary MTC. Together these findings suggest that aberrant CDK5 activity precedes cell cycle initiation and thus may function as a tumor-promoting factor facilitating cell cycle protein expression in MTC. Targeting aberrant CDK5 or its downstream effectors may be a strategy to halt MTC tumorigenesis.

Original languageEnglish (US)
Pages (from-to)12080-12093
Number of pages14
JournalOncotarget
Volume6
Issue number14
DOIs
StatePublished - 2015

Keywords

  • Cdk5
  • Cell cycle
  • Medullary thyroid carcinoma
  • Neuroendocrine
  • Retinoblastoma protein

ASJC Scopus subject areas

  • Oncology

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