Acetylation control of the retinoblastoma tumour-suppressor protein

The retinoblastoma tumour-suppressor protein (pRb) and p300/CBP co-activato r proteins are important for control of proliferation and in tumour cells t hese are sequestered by viral oncoproteins such as E1A, pRb is involved in negatively regulating growth, and p300/CBP proteins have histone acetyltran sferase (HAT) activity, which influences gene expression. Although it is kn own that phosphorylation by G1 cyclin-dependent kinases (CDKs) regulates pR b activity, the nature and role of other post-translational modifications i s not understood. Here we identify acetylation as a new type of modificatio n and level of control in pRb function. Adenovirus E1A, which binds p300/CB P through an amino-terminal transformation-sensitive domain, stimulates the acetylation of pRb by recruiting p300 and pRb into a multimeric-protein co mplex. Furthermore, pRb acetylation is under cell-cycle control, and acetyl ation hinders the phosphorylation of pRb by cyclin-dependent kinases, pRb b inds more strongly when acetylated to the MDM2 oncoprotein, which indicates that acetylation may regulate protein-protein interactions in the pRb path way. The acetylation of pRb defines a new level of cell-cycle control media ted by HAT. Furthermore, our results establish a relationship between p300, pRb and acetylation in which E1A acts to recruit and target a cellular HAT activity to pRb.