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RBP1 Family Proteins Exhibit SUMOylation-Dependent Transcriptional Repression and Induce Cell Growth Inhibition Reminiscent of Senescence

Department of Biochemistry,¹ Department of Oncology,² McGill Cancer Center, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada³

Received 29 June 2005/ Returned for modification 23 August 2005/ Accepted 5 December 2005

The retinoblastoma binding protein 1 (RBP1) appears to be an important factor in the repression of E2F-dependent transcription by the retinoblastoma protein (pRB) family. The recent identification of the breast carcinoma associated antigen (BCAA) as an RBP1-like protein led us to investigate its biological properties and compare them to RBP1. Like RBP1, BCAA contains a carboxy-terminal R2 domain that elicits histone deacetylase (HDAC)-dependent transcriptional repression via interactions with the SAP30 subunit of the Sin3/HDAC complex. Each RBP1 family member also contains two HDAC-independent repression activities within a region termed R1, which can be subdivided into a SUMOylated moiety (R1) and a predicted -helical region (R1). R1 is embedded within the ARID region and represses basal transcription only, whereas R1 represses both basal and activated transcription and depends on SUMOylation. Overexpression of either RBP1 or BCAA, but not the truncated BCAA^MCF-7 isoform that is overexpressed in breast cancer cells, caused a profound inhibition of cell proliferation and induced expression of a senescence marker. In each case the presence of both R1 and R2 was necessary for suppression of cell growth, suggesting that both R1 and R2 transcriptional repression activities play a role in RBP1 family protein-mediated regulation of cellular proliferation.

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