The RNA-binding protein Sam68 is a multifunctional player in human cancer

Department of Public Health and Cell Biology, University of Rome Tor Vergata, Italy.
Endocrine Related Cancer (Impact Factor: 4.81). 05/2011; 18(4):R91-R102. DOI: 10.1530/ERC-11-0041
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Src associated in mitosis, of 68 kDa (Sam68) is a KH domain RNA-binding protein that belongs to the signal transduction and activation of RNA family. Although ubiquitously expressed, Sam68 plays very specialized roles in different cellular environments. In most cells, Sam68 resides in the nucleus and is involved in several steps of mRNA processing, from transcription, to alternative splicing, to nuclear export. In addition, Sam68 translocates to the cytoplasm upon cell stimulation, cell cycle transitions or viral infections, where it takes part to signaling complexes and associates with the mRNA translation machinery. Recent evidence has linked Sam68 function to the onset and progression of endocrine tumors, such as prostate and breast carcinomas. Notably, all the biochemical activities reported for Sam68 seem to be implicated in carcinogenesis. Herein, we review the recent advancement in the knowledge of Sam68 function and regulation and discuss it in the frame of its participation to neoplastic transformation and tumor progression.

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Available from: Maria Paola Paronetto, Sep 24, 2014
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    • "Further the Sam68 and SRSF1 splice factors are implicated in PCa (see above) and in other cancers they are connected to PI3K signaling. Sam68 can be activated through phosphorylation by ERK.92 SRSF1 activates mTORC1 in lung cancer85 and its function can be regulated through phosphorylation by AKT.93 Altogether, based on data from prostate and other cancers, it is tempting to speculate that the AR and PI3K pathways may be densely populated with splicing regulatory networks. Importantly, since these pathways are currently the main targets for treatment of advanced PCa, understanding of the potential splicing networks will be critical. "
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    ABSTRACT: Alternative splicing (AS) is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer (PCa) AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa: androgen receptor (AR) and phosphoinositide 3-kinase (PI3K). These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.
    Asian Journal of Andrology 05/2014; 16(4). DOI:10.4103/1008-682X.127825 · 2.60 Impact Factor
    • "This scenario is further complicated by the involvement of another splicing regulator, Sam68. Sam68, the 68 kD Src-associated protein in mitosis, is a member of the STAR (signal transduction and activation of RNA) family of RNA-binding proteins [66]. It contains a single KH-type RNA-binding domain and several protein-protein interaction motifs including potential binding sites for SH2, SH3, and WW domains, which are characteristic of signaling transducers [67]. "
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    ABSTRACT: Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.
    International Journal of Cell Biology 10/2013; 2013(2):962038. DOI:10.1155/2013/962038
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    • "From that point of view NMR is very powerful because it allows the screening of multiple RNA sequences at an early stage of the structural investigation, as will be detailed in this article for two proteins, Sam68 and T-STAR, that belong to the STAR family of proteins [13,14]. Sam68 is the best-characterised member of this family and is involved in various post-transcriptional regulation events, such as alternative splicing and RNA export [15,16]. T-STAR, also known as SLM2, is closely related to Sam68 but its biological function is less well characterised [17,18]. "
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    ABSTRACT: In the past few years, RNA molecules have been revealed to be at the center of numerous biological processes. Long considered as passive molecules transferring genetic information from DNA to proteins, it is now well established that RNA molecules play important regulatory roles. Associated with that, the number of identified RNA binding proteins (RBP) has increased considerably and mutations in RNA molecules or RBP have been shown to cause various diseases, such as cancers. It is therefore crucial to understand at the molecular level how these proteins specifically recognize their RNA targets in order to design new generation drug therapies targeting protein-RNA complexes. Nuclear Magnetic Resonance (NMR) is a particularly well-suited technique to study such protein-RNA complexes at the atomic level and can provide valuable information for new drug discovery programs. In this chapter, we describe the NMR strategy that we and other laboratories use for screening optimal conditions necessary for structural studies of protein-single stranded RNA complexes, using two proteins, Sam68 and T-STAR, as examples.
    Methods 10/2013; 65(3). DOI:10.1016/j.ymeth.2013.09.018 · 3.65 Impact Factor
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