The Role of Cdk5 in Neuroendocrine Thyroid Cancer
Author(s)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.; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Picower Institute for Learning and Memory
Pozo, Karine, Emely Castro-Rivera, Chunfeng Tan, Florian Plattner, Gert Schwach, Veronika Siegl, Douglas Meyer, et al. “The Role of Cdk5 in Neuroendocrine Thyroid Cancer.” Cancer Cell 24, no. 4 (October 2013): 499–511.
Author's final manuscript