title: Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis.
abstract: Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer of thyroid C-cells, for which few treatment options are available. We have recently reported a role for cyclin-dependent kinase 5 (CDK5) in MTC pathogenesis. We have generated a mouse model, in which MTC proliferation is induced upon conditional overexpression of the CDK5 activator, p25, in C-cells, and arrested by interrupting p25 overexpression. Here, we identify genes and proteins that are differentially expressed in proliferating versus arrested benign mouse MTC. We find that downstream target genes of the tumor suppressor, retinoblastoma protein, including genes encoding cell cycle regulators such as CDKs, cyclins and CDK inhibitors, are significantly upregulated in malignant mouse tumors in a CDK5-dependent manner. Reducing CDK5 activity in human MTC cells down-regulated these cell cycle regulators suggesting that CDK5 activity is critical for cell cycle progression and MTC proliferation. Finally, the same set of cell cycle proteins was consistently overexpressed in human sporadic MTC but not in hereditary MTC. Together these findings suggest that aberrant CDK5 activity precedes cell cycle initiation and thus may function as a tumor-promoting factor facilitating cell cycle protein expression in MTC. Targeting aberrant CDK5 or its downstream effectors may be a strategy to halt MTC tumorigenesis.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Karine
authors.initials: K
authors.lastname: Pozo
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Antje
authors.initials: A
authors.lastname: Hillmann
authors.affiliation: Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA.|Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Augustyn
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Hai
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Tanvir
authors.initials: T
authors.lastname: Singh
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Saleh
authors.initials: S
authors.lastname: Ramezani
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
authors.affiliation: Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Pfragner
authors.affiliation: Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA.|Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Cote
authors.affiliation: Endocrine Surgery Research Laboratory, The University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.affiliation: Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Fiemu E
authors.initials: FE
authors.lastname: Nwariaku
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D018276:Carcinoma, Medullary / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051360:Cyclin-Dependent Kinase 5
keywords: Cdk5; cell cycle; medullary thyroid carcinoma; neuroendocrine; retinoblastoma protein