title: The role of Cdk5 in neuroendocrine thyroid cancer.
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.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Karine
authors.initials: K
authors.lastname: Pozo
authors.forename: Emely
authors.initials: E
authors.lastname: Castro-Rivera
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Tan
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.forename: Gert
authors.initials: G
authors.lastname: Schwach
authors.forename: Veronika
authors.initials: V
authors.lastname: Siegl
authors.forename: Douglas
authors.initials: D
authors.lastname: Meyer
authors.forename: Ailan
authors.initials: A
authors.lastname: Guo
authors.forename: Justin
authors.initials: J
authors.lastname: Gundara
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mettlach
authors.forename: Edmond
authors.initials: E
authors.lastname: Richer
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Guevara
authors.forename: Li
authors.initials: L
authors.lastname: Ning
authors.forename: Anjali
authors.initials: A
authors.lastname: Gupta
authors.forename: Guiyang
authors.initials: G
authors.lastname: Hao
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
authors.forename: Pietro
authors.initials: P
authors.lastname: Antich
authors.forename: Stanley
authors.initials: S
authors.lastname: Sidhu
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
authors.forename: Fiemu E
authors.initials: FE
authors.lastname: Nwariaku
authors.forename: Roswitha
authors.initials: R
authors.lastname: Pfragner
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000818:Animals; D018276:Carcinoma, Medullary / Q000378:metabolism*; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000378:metabolism*; D013997:Time Factors; D019076:Transgenes
chemical_list: D016160:Retinoblastoma Protein; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human