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  • Original Paper
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Differences in stability of repressor complexes at promoters underlie distinct roles for Rb family members

Oncogene volume 23, pages 814–823 (2004)Cite this article

Abstract

Oncogenic transformation of cells can induce the cyclin-dependent kinase inhibitor, p16, which leads to hypophosphorylation and activation of retinoblastoma (Rb). Rb is capable of causing permanent growth arrest, which may underlie its role as a tumor suppressor. We show that repression by Rb at E2F target gene promoters involves the establishment of a stable repressor complex that is not displaced by the overexpression of E2F-1. Rather than displacing Rb, excess E2F-1 instead recruits more Rb, leading to direct transcriptional repression. In contrast, the Rb family members, p130 and p107, which have not been demonstrated to be tumor suppressors, bind preferentially to target promoters in the absence of growth factors and in proliferating cells, respectively, and these repressor complexes are displaceable by E2F-1. Heterochromatin protein 1 (HP1), which interacts with Rb, is associated with these distinct repressor complexes and follows a similar pattern of stability/displaceability. Efficient growth arrest by p16/Rb is dependent on histone H3 lysine 9 methylation, which provides a binding site for HP1. We propose that these differences in the stability of repressor complexes at promoters may, in part, underlie the different roles of Rb vs p130 and p107 in cell cycle regulation and tumor suppression.

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Acknowledgements

We thank Jason Weber for helpful comments on the manuscript; Gordon Peters for EH1 cells; Kristian Helin for anti-E2F1 amino-terminus antibody and pBabeHAERE2F1; Gerard Evan for the tamoxifen-responsive estrogen receptor construct; David Johnson for GST-E2F1; Tyler Jacks for Rb−/− MEFs; Thomas Jenuwein for Suv39H1/H2 double knockout cells; and Douglas Dean for previous intellectual contribution and support. This work was supported by grants from the National Institutes of Health (CA 85839) and the American Heart Association (EI9940116N) to GDL.

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  1. Departments of Medicine and Cell Biology, Washington University School of Medicine, St Louis, 63110, MO, USA

    Arthur P Young & Gregory D Longmore

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Correspondence to Gregory D Longmore.

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Young, A., Longmore, G. Differences in stability of repressor complexes at promoters underlie distinct roles for Rb family members. Oncogene 23, 814–823 (2004). https://doi.org/10.1038/sj.onc.1207187

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