NF-kappa B-dependent induction of cyclin D1 by retinoblastoma protein (pRB) family proteins and tumor-derived pRB mutants.
The retinoblastoma protein (pRB) and its homologues, p107 and p130, prevent cell cycle progression from G(0)/G(1) to S phase by forming complexes with E2F transcription factors. Upon phosphorylation by G(1) 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-kappaB 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-kappaB and inducers of G(1) cyclin. Certain pRB pocket mutants may give rise to a cellular situation in which deregulated E2F and cyclin D1 cooperatively promote abnormal cell proliferation.
Takebayashi
Tetsuro
T
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan. mhata@imm.hokudai.ac.jp
Higashi
Hideaki
H
Sudo
Hideki
H
Ozawa
Heita
H
Suzuki
Etsu
E
Shirado
Osamu
O
Katoh
Hiroyuki
H
Hatakeyama
Masanori
M
D017500:Adenovirus E1A Proteins / Q000494:pharmacology; D002455:Cell Division; D019938:Cyclin D1 / Q000096:biosynthesis*; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D011506:Proteins; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology*; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D014162:Transfection; D014407:Tumor Cells, Cultured
D017500:Adenovirus E1A Proteins; C534702:CCNG1 protein, human; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; C493844:RBL1 protein, human; C493837:RBL2 protein, human; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D019938:Cyclin D1