The Role of Cdk5 in Neuroendocrine Thyroid Cancer

• Published in: Cancer cell Vol. 24; no. 4; pp. 499 - 511
• Main Authors: Pozo, Karine, Castro-Rivera, Emely, Tan, Chunfeng, Plattner, Florian, Schwach, Gert, Siegl, Veronika, Meyer, Douglas, Guo, Ailan, Gundara, Justin, Mettlach, Gabriel, Richer, Edmond, Guevara, Jonathan A., Ning, Li, Gupta, Anjali, Hao, Guiyang, Tsai, Li-Huei, Sun, Xiankai, Antich, Pietro, Sidhu, Stanley, Robinson, Bruce G., Chen, Herbert, Nwariaku, Fiemu E., Pfragner, Roswitha, Richardson, James A., Bibb, James A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-10-2013
• Subjects: Animals; Carcinoma, Medullary - metabolism; Carcinoma, Neuroendocrine - metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase 5 - metabolism; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Transgenic; Phosphorylation; Retinoblastoma Protein - metabolism; Signal Transduction; Thyroid Neoplasms - metabolism; Time Factors; Transgenes
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2013.08.027

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.
•Cdk5 and its activators are expressed in human MTC•Cdk5 activity drives proliferation of sporadic human MTC cell lines•Transgenic expression of the Cdk5 cofactor p25 rapidly induces lethal MTC in mice•Rb phosphorylation at Ser807/Ser811 is critical for MTC progression