The Role of Cdk5 in Neuroendocrine Thyroid Cancer

• 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

SummaryMedullary 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.