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Acetylation control of the retinoblastoma tumour-suppressor protein

Nature Cell Biology volume 3, pages 667–674 (2001)Cite this article

Abstract

The retinoblastoma tumour-suppressor protein (pRb) and p300/CBP co-activator proteins are important for control of proliferation and in tumour cells these are sequestered by viral oncoproteins such as E1A. pRb is involved in negatively regulating growth, and p300/CBP proteins have histone acetyltransferase (HAT) activity, which influences gene expression. Although it is known that phosphorylation by G1 cyclin-dependent kinases (CDKs) regulates pRb activity, the nature and role of other post-translational modifications is not understood. Here we identify acetylation as a new type of modification and level of control in pRb function. Adenovirus E1A, which binds p300/CBP through an amino-terminal transformation-sensitive domain, stimulates the acetylation of pRb by recruiting p300 and pRb into a multimeric-protein complex. Furthermore, pRb acetylation is under cell-cycle control, and acetylation hinders the phosphorylation of pRb by cyclin-dependent kinases. pRb binds more strongly when acetylated to the MDM2 oncoprotein, which indicates that acetylation may regulate protein–protein interactions in the pRb pathway. The acetylation of pRb defines a new level of cell-cycle control mediated 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.

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Figure 1: The retinoblastoma protein is modified by acetylation.
Figure 2: The C-terminal region of pRb is a main site of acetylation.
Figure 3: Adenovirus E1A increases p300-dependent acetylation of pRb.
Figure 4: Domains in E1A for p300-dependent acetylation of pRb, and acetylated pRb binds to MDM2.
Figure 5: Functional effects of pRb acetylation.
Figure 6: Regulation of pRb acetylation during cell-cycle progression and differentiation.

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Acknowledgements

We thank P. Adams, L. Bandara, J. Gannon, B. Kaelin, S. Mittnacht and Y. Nakatani for providing reagents, L. Delavaine for His–E1A, M. Caldwell for assistance in preparing the manuscript, and the Medical Research Council, the Wellcome Trust, the Leukaemia Research Fund and European Union for supporting this research.

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  1. Division of Biochemistry and Molecular Biology, Davidson Building, University of Glasgow, Glasgow, G12 8QQ, UK

    Ho Man Chan, Marija Krstic-Demonacos, Linda Smith, Constantinos Demonacos & Nicholas B. La Thangue

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  1. Ho Man Chan
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Correspondence to Nicholas B. La Thangue.

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Table S1 Numerical data for Fig. 5c (PDF 27 kb)

Table S2 Effect of p300 alone

Table S3 Examples of numerical data taken from other experiments

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Chan, H., Krstic-Demonacos, M., Smith, L. et al. Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Cell Biol 3, 667–674 (2001). https://doi.org/10.1038/35083062

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