Regulation of Splicing through Sam68
While transcriptional regulation is often viewed as the most prevalent way extracellular signals to regulate gene expression, post-transcriptional regulation of splicing, RNA stability, and translation are also regulated by extracellular signals. Sam68, a member of a family of RNA-binding proteins called STAR proteins, mediates alternative splicing in response to extracellular signals, such as altered splicing of CD44 in response to phorbol ester treatment of T cells. RNA binding and activity of SAM68 is regulated by upstream signals through phosphorylation and modulating of its interaction with other proteins, itself and with RNA. Phorbol ester treatment of T cells stimulates the ras/ Map kinase pathway, activating Erk and phosphorylation of Sam68, inducing alternative splicing of CD44 and perhaps other cellular RNA targets. Sam68 is localized in the nucleus to a specific substructure called the Sam68/SLM Nuclear Bodies, colocalizing with splicing factors and helping to link perhaps signal transduction with RNA processing. Sam68 has been suggested to play a role in a variety of pathways, including insulin signaling and HIV gene expression, substituting for the activity of viral Rev protein, and to be regulated by arginine methylation as well as phosphorylation. In addition to the role of Sam68 regulating posttranscriptional gene expression, Sam68 also interacts with transcription factors such as CBP and appears to regulate gene expression.Sam68 also appears to play a role in cell cycle progression through influencing RNA processing. During mitosis SAM68 is tyrosine phosphorylated and associated with Src. The interaction of Sam68 with RNA is repressed by this phosphorylation, whereas interaction of Sam68 with Ras-GAP is stimulated by phosphorylation. Sam68 appears to be downregulated in tumors and transformed cells and its expression is reduced during mitosis, suggesting it inhibits proliferation. The RNA binding domain in Sam68, called a KH domain, is absent in a splice isoform that is expressed in cells that display contact inhibition of cellular growth. Sam68 with the KH domain appears in some settings to stimulate the G1/S transition, while blocking mitosis in some reports.
Contributor: Glenn Croston, PhD
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