Retinoblastoma protein represses transcription by recruiting a histone deacetylase

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Abstract

The retinoblastoma tumour-suppressor protein Rb1 inhibits cell proliferation by repressing a subset of genes that are controlled by the E2F family of transcription factors2 and which are involved in progression from the G1 to the S phase of the cell cycle. Rb, which is recruited to target promoters by E2F1 (ref. 3), represses transcription by masking the E2F1 transactivation domain4 and by inhibiting surrounding enhancer elements5,6,7,8, an active repression that could be crucial for the proper control of progression through the cell cycle9. Some transcriptional regulators act by acetylating or deacetylating the tails protruding from the core histones10, thereby modulating the local structure of chromatin: for example, some transcriptional repressors function through the recruitment of histone deacetylases11. We show here that the histone deacetylase HDAC1 physically interacts and cooperates with Rb. In HDAC1, the sequence involved is an LXCXE motif, similar to that used by viral transforming proteins to contact Rb. Our results strongly suggest that the Rb/HDAC1 complex is a key element in the control of cell proliferation and differentiation and that it is a likely target for transforming viruses.

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Figure 1: A histone deacetylase activity is associated with Rb.
Figure 2: Rb interacts with HDAC1 through an ‘LXCXE’-like motif.
Figure 3: Rb interacts simultaneously with E2F1 and HDAC1.
Figure 4: HDAC1 cooperates with Rb to repress E2F1 activity.

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Acknowledgements

This paper is dedicated to the memory of Jacques G. Harel who originated this work. We thank N. La Thangue, W. Kaelin, T. Kouzarides, C. Hassig, E. Lam, S. A. Leibovitch, R. Watson, S.Schreiber and S.Khochbin for materials, and C. Jaulin, G. Almouzni, S. Kochbin and L. Pritchard for discussion. This work was supported by grants from the Ligue Nationale contre le Cancer, the Comité des Yvelines and theComité du Val de Marne, from the Association pour la Recherche sur le Cancer and from the Groupement des Entreprises Francaises dans la Lutte contre le Cancer. L.M.J. held a fellowship from the Société Française du Cancer; R.G. held a fellowship from the Association Française contre les Myopathies.

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Correspondence to A. Harel-Bellan.

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Magnaghi-Jaulin, L., Groisman, R., Naguibneva, I. et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391, 601–605 (1998) doi:10.1038/35410

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