Regulation of E2F1 function by the nuclear corepressor KAP1.
KAP1 is a nuclear corepressor with conserved domains for RING finger, B boxes, leucine zipper alpha helical coiled-coil region, plant homeo domain finger, and bromo domain. The plant homeo domain finger and bromo domain of KAP1 cooperatively function as a transcription repression domain by recruiting the histone deacetylase complex NuRD and histone H3 lysine 9-specific methyltransferase SETDB1. Here we report that KAP1 binds the E2F1 transcription factor in a retinoblastoma protein (pRb)-independent fashion and inhibits E2F1 activity. KAP1 stimulates formation of E2F1-HDAC1 complex and inhibits E2F1 acetylation. Ectopic expression of KAP1 represses E2F1 transcription and apoptosis functions independent of pRb. Depletion of endogenous KAP1 in pRb-deficient Saos2 cells by RNA interference increases E2F1 acetylation level, stimulates E2F1 transcriptional activity, and sensitizes apoptosis response to DNA damage. Therefore, KAP1 contributes to the negative regulation of E2F1 and may serve as a partial backup to prevent E2F1-mediated apoptosis in the absence of pRb.
Wang
Chuangui
C
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Rauscher
Frank J
FJ
Cress
W Douglas
WD
Chen
Jiandong
J
D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014162:Transfection; D000076183:Tripartite Motif-Containing Protein 28
D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28