Versatility of RNA-Binding Proteins in Cancer

Abstract

Posttranscriptional gene regulation is a rapid and efficient process to adjust the proteome of a cell to a changing environment. RNA-binding proteins (RBPs) are the master regulators of mRNA processing and translation and are often aberrantly expressed in cancer. In addition to well-studied transcription factors, RBPs are emerging as fundamental players in tumor development. RBPs and their mRNA targets form a complex network that plays a crucial role in tumorigenesis. This paper describes mechanisms by which RBPs influence the expression of well-known oncogenes, focusing on precise examples that illustrate the versatility of RBPs in posttranscriptional control of cancer development. RBPs appeared very early in evolution, and new RNA-binding domains and combinations of them were generated in more complex organisms. The identification of RBPs, their mRNA targets, and their mechanism of action have provided novel potential targets for cancer therapy.

Figure 1

Schematic representation of the 4 RBPs discussed in this paper: Sam68, eIF4E, La, and HuR; RBDs are depicted in light gray. RRM: RNA recognition motif; GSG: GRP33/SAM68/GLD-1 domain, composed of a KH domain (KH) flanked by N-terminal (NK) and C-terminal (CK) extensions; LA: La motif. Phosphorylation sites of La are indicated in black (P0–P5). Nuclear localization signals (NLSs) are represented in dark gray. The number of amino acids of each protein is indicated.

Figure 2

Overview of posttranscriptional gene regulation by Sam68, eIF4E, La, and HuR in tumorigenesis. In cancer cells, RBPs are posttranslationally modified by aberrantly active signaling pathways that activate their binding to targets encoding proteins implicated in tumorigenesis. The steps of mRNA metabolism regulated by RBPs are indicated. (+) and (–) specify up- or downregulation. P and CH₃–CO indicate phosphorylation and acetylation of RBPs. EMT: epithelial to mesenchymal transition.

Figure 3

Conservation of Sam68, eIF4E, La, and HuR in different phyla. Phylogenetic tree of the RBPs described in this paper. The presence of homologues is indicated.