The Role of Cdk5 in Neuroendocrine Thyroid Cancer

Karine Pozo, Emely Castro-Rivera, Chunfeng Tan, Florian Plattner, Gert Schwach, Veronika Siegl, Douglas Meyer, Ailan Guo, Justin Gundara, Gabriel Mettlach, Edmond Richer, Jonathan A. Guevara, Li Ning, Anjali Gupta, Guiyang Hao, Li Huei Tsai, Xiankai Sun, Pietro Antich, Stanley Sidhu, Bruce G. RobinsonHerbert Chen, Fiemu E. Nwariaku, Roswitha Pfragner, James A. Richardson, James A. Bibb

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.

Original languageEnglish (US)
Pages (from-to)499-511
Number of pages13
JournalCancer Cell
Volume24
Issue number4
DOIs
StatePublished - Oct 14 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Pozo, K., Castro-Rivera, E., Tan, C., Plattner, F., Schwach, G., Siegl, V., Meyer, D., Guo, A., Gundara, J., Mettlach, G., Richer, E., Guevara, J. A., Ning, L., Gupta, A., Hao, G., Tsai, L. H., Sun, X., Antich, P., Sidhu, S., ... Bibb, J. A. (2013). The Role of Cdk5 in Neuroendocrine Thyroid Cancer. Cancer Cell, 24(4), 499-511. https://doi.org/10.1016/j.ccr.2013.08.027