Acetylation regulates the differentiation-specific functions of the retinoblastoma protein.
The retinoblastoma tumor-suppressor protein (pRb) is known to induce growth arrest and cellular differentiation. The molecular determinants of pRb function include protein-protein interactions and post-translational modifications such as phosphorylation. Recently, the co-activator p300 was found to acetylate pRb. The biological significance of pRb acetylation, however, remains unclear. In the present study, we provide evidence that pRb undergoes acetylation upon cellular differentiation, including skeletal myogenesis. In addition to p300, the p300-Associated Factor (P/CAF) can mediate pRb acetylation as pRb interacts directly with the acetyltransferase domain of P/CAF in vitro and can associate with P/CAF in differentiated cells. Significantly, by using a C terminal acetylation-impaired mutant of pRb, we reveal that acetylation does not affect pRb-dependent growth arrest or the repression of E2F transcriptional activity. Instead, acetylation is required for pRb-mediated terminal cell cycle exit and the induction of late myogenic gene expression. Based on these results, we propose that acetylation regulates the differentiation-specific function(s) of pRb.
Nguyen
Don X
DX
Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA.
Baglia
Laurel A
LA
Huang
Shih-Min
SM
Baker
Christina M
CM
McCance
Dennis J
DJ
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D050684:E2F Transcription Factors; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D017500:Adenovirus E1A Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein; D050684:E2F Transcription Factors; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C416925:EID1 protein, human; C494361:Ep300 protein, mouse; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse