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J. Biol. Chem., Vol. 278, Issue 17, 14897-14905, April 25, 2003

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NF-B-dependent Induction of Cyclin D1 by Retinoblastoma Protein (pRB) Family Proteins and Tumor-derived pRB Mutants^*

Tetsuro Takebayashi, Hideaki Higashi, Hideki Sudo, Heita Ozawa, Etsu Suzuki^§, Osamu Shirado^¶, Hiroyuki Katoh, and Masanori Hatakeyama^**

From the  Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, the ^§ Division of Nephrology and Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, the ^¶ Department of Orthopedic Surgery, and the  Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

The retinoblastoma protein (pRB) and its homologues, p107 and p130, prevent cell cycle progression from G₀/G₁ to S phase by forming complexes with E2F transcription factors. Upon phosphorylation by G₁ cyclin-cyclin-dependent kinase (Cdk) complexes such as cyclin D1-Cdk4/6 and cyclin E-Cdk2, they lose the ability to bind E2F, and cells are thereby allowed to progress into S phase. Functional loss of one or more of the pRB family members, as a result of genetic mutation or deregulated phosphorylation, is considered to be an essential prerequisite for cellular transformation. In this study, we found that pRB family proteins have the ability to stimulate cyclin D1 transcription by activation of the NF-B transcription factor. The cyclin D1-inducing activity of pRB is abolished by adenovirus E1A oncoprotein but not by the deletion of the A-box, the B-box, or the C-terminal region of the pocket, indicating that multiple pocket sequences are independently involved in cyclin D1 activation. Intriguingly, tumor-derived pRB pocket mutants retain the cyclin D1-inducing activity. Our results reveal a novel role of pRB family proteins as potential activators of NF-B and inducers of G₁ cyclin. Certain pRB pocket mutants may give rise to a cellular situation in which deregulated E2F and cyclin D1 cooperatively promote abnormal cell proliferation.

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