Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression.
The potential tumor suppressor protein prohibitin can prevent cell proliferation and this required its binding to the Rb protein. Prohibitin could repress the transcriptional activity of E2F family members and this required a part of the marked box region of E2F. The sub-cellular localization of prohibitin has been variously attributed to the mitochondria as well as the inner cell membrane. Here we show that a subset of prohibitin molecules are present in the nucleus where it co-localizes with the Rb protein. Deletion of a putative amino-terminal membrane-docking domain of prohibitin had no effect on its ability to suppress cell proliferation or inhibit E2F activity. Our experiments show that a 53 amino-acid stretch of E2F1 is sufficient for being targeted by prohibitin; fusion of this region to GAL4-VP16 construct could make it susceptible to prohibitin-mediated, but not Rb-mediated repression. Prohibitin, like Rb, could repress transcription from SV40 and major late promoters when recruited directly to DNA. Prohibitin mediated transcriptional repression required histone-deacetylase activity, but unlike Rb, additional co-repressors like N-CoR are also involved. Repression by prohibitin correlates with histone deacetylation on promoters and this was reversed by IgM stimulation of cells; IgM did not affect Rb-mediated repression or deacetylation of the promoters. Prohibitin thus appears to repress E2F-mediated transcription utilizing different molecular mediators and facilitate channeling of specific signaling pathways to the cell cycle machinery.
Wang
Sheng
S
Department of Interdisciplinary Oncology, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa 33612, USA.
Fusaro
Gina
G
Padmanabhan
Jaya
J
Chellappan
Srikumar P
SP
D001483:Base Sequence; D001943:Breast Neoplasms; D002467:Cell Nucleus / Q000502:physiology*; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D056971:Nuclear Receptor Co-Repressor 1; D000091402:Prohibitins; D011506:Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D017931:DNA Primers; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D000091402:Prohibitins; D011506:Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases