Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function.
The retinoblastoma tumor suppressor protein and its family members, p107 and p130, are major regulators of the mammalian cell cycle. They exert their growth suppressive effects at least in part by binding the E2F family of transcription factors and inhibiting their transcriptional activity. Agents that disrupt the interaction between Rb family proteins and E2F promote cell proliferation. Here we describe the characterization of a novel interaction between Rb family proteins and a potential tumor suppressor protein, prohibitin. Prohibitin physically interacts with all three Rb family proteins in vitro and in vivo, and was very effective in repressing E2F-mediated transcription. Prohibitin could inhibit the activity of E2Fs 1, 2, 3, 4 and 5, but could not affect the activity of promoters lacking an E2F site. Surprisingly, prohibitin-mediated repression of E2F could not be reversed by adenovirus E1A protein. A prohibitin mutant that could not bind to Rb was impaired in its ability to repress E2F activity and inhibit cell proliferation. We believe that prohibitin is a novel regulator of E2F activity that responds to specific signaling cascades.
Wang
S
S
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Nath
N
N
Adlam
M
M
Chellappan
S
S
D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D000091402:Prohibitins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000502:physiology*; D056465:Retinoblastoma-Binding Protein 1; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000091402:Prohibitins; D011506:Proteins; C493844:RBL1 protein, human; C493837:RBL2 protein, human; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors