Oncotarget

Research Papers:

Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis

Karine Pozo _, Antje Hillmann, Alexander Augustyn, Florian Plattner, Tao Hai, Tanvir Singh, Saleh Ramezani, Xiankai Sun, Roswitha Pfragner, John D. Minna, Gilbert J. Cote, Herbert Chen, James A. Bibb and Fiemu E. Nwariaku

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Oncotarget. 2015; 6:12080-12093. https://doi.org/10.18632/oncotarget.3813

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Abstract

Karine Pozo1, Antje Hillmann1, Alexander Augustyn2,3, Florian Plattner1, Tao Hai4, Tanvir Singh1, Saleh Ramezani5, Xiankai Sun5, Roswitha Pfragner6, John D. Minna2,3,7, Gilbert J. Cote4, Herbert Chen8, James A. Bibb1,5,9,* and Fiemu E. Nwariaku10,*

1 Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA

2 Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA

3 Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA

4 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

5 Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

6 Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria

7 Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

8 Endocrine Surgery Research Laboratory, The University of Wisconsin Carbone Cancer Center, Madison, WI, USA

9 Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, USA

10 Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, USA

* These authors have contributed equally to this work

Correspondence to:

James A. Bibb, email:

Karine Pozo, email:

Keywords: Cdk5, retinoblastoma protein, neuroendocrine, medullary thyroid carcinoma, cell cycle

Received: August 26, 2014 Accepted: March 03, 2015 Published: April 14, 2015

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.


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