Mini Review
The RB/E2F pathway and regulation of RNA processing

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Abstract

The retinoblastoma tumor suppressor protein (RB) is inactivated in a majority of cancers. RB restricts cell proliferation by inhibiting the E2F family of transcription factors. The current model for RB/E2F function describes its role in regulating transcription at gene promoters. Whether the RB or E2F proteins might play a role in gene expression beyond transcription initiation is not well known. This review describes evidence that points to a novel role for the RB/E2F network in the regulation of RNA processing, and we propose a model as a framework for future research. The elucidation of a novel role of RB in RNA processing will have a profound impact on our understanding of the role of this tumor suppressor family in cell and developmental biology.

Introduction

The retinoblastoma tumor suppressor protein (RB) is mutated or inactivated in a majority of cancers, and therefore its function has been the subject of much investigation. RB is highly conserved among metazoans and is a major component of the cell cycle, and it has a central role in development and differentiation. Thus, a detailed understanding of RB function is important to biology and medicine. The best described function of RB is to restrict cell proliferation by suppressing gene expression through direct inhibition of the E2F family of transcription factors [1]. The current model for RB/E2F network function describes its role in modulating gene expression at promoters. However, the question of whether the RB or E2F proteins play a role in gene expression beyond transcription initiation has never been systematically addressed. This review describes several lines of evidence that point to a novel role for the RB/E2F network in the regulation of RNA processing.

Section snippets

RB interacts with RNA-binding proteins

The RB protein has no known enzymatic function; its primary function is thought to be in coordinating the binding of different proteins to form diverse multiprotein complexes. Much work has been done to identify binding partners of RB in order to better understand its function in the regulation of cellular processes [2]. Among the many proteins identified are several RNA-binding proteins (Table 1). The proteins listed in Table 1 have been shown to affect a wide range of processes during RNA

The RB/E2F pathway regulates RNA processing

Interesting observations have emerged which support a model involving the RB/E2F pathway in RNA processing either indirectly through transcriptional regulation of RNA-binding proteins or by direct physical interaction with RNA processing factors. Mammalian studies have shown that E2F can regulate the production of splicing factors [28], [29]. One study identified SC35, a member of the SR family of splicing factors, as a direct transcriptional target of E2F1. Significantly, SC35 is required for

Coupling of transcription and RNA processing

Transcription and RNA processing have commonly been considered as separate events. Consequently, transcription factors are generally examined for their ability to upregulate or downregulate transcription of target genes without giving much consideration to transcript processing. However, mounting evidence supports a model that integrates transcription initiation with downstream processing events, including pre-mRNA splicing. For example, placing a different promoter sequence upstream of a gene

Conclusion

The RB tumor suppressor protein interacts with RNA processing factors that help it to regulate a diverse array of processes (Figure 2B). Future experiments will reveal how the retinoblastoma tumor suppressor might influence RNA splicing, transport, and stability. The elucidation of a novel role of RB in RNA processing will have a profound impact on our understanding of the role of this tumor suppressor family in cell and developmental biology, and it will place this versatile protein at almost

Acknowledgments

This work was supported by the National Institutes of Health grant GM069462. We thank Maureen Peterson for helpful comments during the preparation of this manuscript.

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