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

• Published in: The Journal of biological chemistry 2003-04, Vol.278 (17), p.14897-14905
• Main Authors: Takebayashi, Tetsuro, Higashi, Hideaki, Sudo, Hideki, Ozawa, Heita, Suzuki, Etsu, Shirado, Osamu, Katoh, Hiroyuki, Hatakeyama, Masanori
• Format: Article
• Language: English
• Subjects: Adenovirus E1A Proteins - pharmacology; Cell Division; Cyclin D1 - biosynthesis; Cyclin G; Cyclin G1; Cyclins - biosynthesis; Gene Expression Regulation; Humans; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; NF-kappa B - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Phosphoproteins - genetics; Phosphoproteins - physiology; Proteins; Retinoblastoma Protein - genetics; Retinoblastoma Protein - physiology; Retinoblastoma-Like Protein p107; Retinoblastoma-Like Protein p130; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; Transfection; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M210849200

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 G1cyclin-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-κB 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-κB 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.