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Molecular and Cellular Biology, July 2006, p. 5449-5469, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02074-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cyclin D1 Determines Mitochondrial Function In Vivo

Toshiyuki Sakamaki,² Mathew C. Casimiro,¹ Xiaoming Ju,¹ Andrew A. Quong,¹ Sanjay Katiyar,¹ Manran Liu,¹ Xuanmao Jiao,¹ Anping Li,¹ Xueping Zhang,¹ Yinan Lu,¹ Chenguang Wang,¹ Stephen Byers,² Robert Nicholson,⁴ Todd Link,⁵ Melvin Shemluck,⁶ Jianguo Yang,¹ Stanley T. Fricke,^2,3 Phyllis M. Novikoff,⁷ Alexandros Papanikolaou,⁸ Andrew Arnold,⁸ Christopher Albanese,² and Richard Pestell^1*

Kimmel Cancer Center, Departments of Cancer Biology and Medical Oncology,¹ Department of Oncology, Lombardi Comprehensive Cancer Center,² Department of Neuroscience, Georgetown University Medical Center, Washington, D.C. 20057,³ Lyman Conservatory, Smith College, Northampton, Massachusetts 01063,⁴ Department of Chemistry, Portland State University, Portland, Oregon 97207,⁵ Biochemistry Department, Quinsigamond Community College, Worcester, Massachusetts 01606,⁶ Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461,⁷ Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut06030-3101⁸

Received 25 October 2005/ Returned for modification 22 November 2005/ Accepted 11 April 2006

The cyclin D1 gene encodes a regulatory subunit of the holoenzyme that phosphorylates and inactivates the pRb tumor suppressor to promote nuclear DNA synthesis. cyclin D1 is overexpressed in human breast cancers and is sufficient for the development of murine mammary tumors. Herein, cyclin D1 is shown to perform a novel function, inhibiting mitochondrial function and size. Mitochondrial activity was enhanced by genetic deletion or antisense or small interfering RNA to cyclin D1. Global gene expression profiling and functional analysis of mammary epithelial cell-targeted cyclin D1 antisense transgenics demonstrated that cyclin D1 inhibits mitochondrial activity and aerobic glycolysis in vivo. Reciprocal regulation of these genes was observed in cyclin D1-induced mammary tumors. Cyclin D1 thus integrates nuclear DNA synthesis and mitochondrial function.

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* Corresponding author. Mailing address: Departments of Cancer Biology, Thomas Jefferson University, BLSB, Room 1050, 233 South 10th Street, Philadelphia, PA 19107. Phone: (215) 503-5649. Fax: (215) 503-9334. E-mail: Richard.Pestell{at}jefferson.edu. E-mail address for reprint requests: D_Scardino{at}mail.jci.tju.edu.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, July 2006, p. 5449-5469, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02074-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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