Sam68, the KH domain-containing superSTAR

Lukong, Kiven Erique; Richard, Stéphane

doi:10.1016/j.bbcan.2003.09.001

Cited by 191 publications

(275 citation statements)

References 105 publications

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“…29,30 In spite of the increasing number of studies reporting a role of SAM68 in human cancer, 17,31 the mechanism(s) of action of this protein in neoplastic cells is still largely unknown. As the activity and subcellular localization of SAM68 is influenced by its interaction with other proteins, 32,33 in the present work we set out to identify proteins that may affect SAM68 activity in PCa cells. Co-immunoprecipitation and mass spectrometry analyses allowed us to identify SND1 (Tudor-SN; p100) as a novel SAM68-interacting protein.…”

Section: Introductionmentioning

confidence: 99%

The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

et al. 2013

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Splicing abnormalities have profound impact in human cancer. Several splicing factors, including SAM68, have pro-oncogenic functions, and their increased expression often correlates with human cancer development and progression. Herein, we have identified using mass spectrometry proteins that interact with endogenous SAM68 in prostate cancer (PCa) cells. Among other interesting proteins, we have characterized the interaction of SAM68 with SND1, a transcriptional co-activator that binds spliceosome components, thus coupling transcription and splicing. We found that both SAM68 and SND1 are upregulated in PCa cells with respect to benign prostate cells. Upregulation of SND1 exerts a synergic effect with SAM68 on exon v5 inclusion in the CD44 mRNA. The effect of SND1 on CD44 splicing required SAM68, as it was compromised after knockdown of this protein or mutation of the SAM68-binding sites in the CD44 pre-mRNA. More generally, we found that SND1 promotes the inclusion of CD44 variable exons by recruiting SAM68 and spliceosomal components on CD44 pre-mRNA. Inclusion of the variable exons in CD44 correlates with increased proliferation, motility and invasiveness of cancer cells. Strikingly, we found that knockdown of SND1, or SAM68, reduced proliferation and migration of PCa cells. Thus, our findings strongly suggest that SND1 is a novel regulator of alternative splicing that promotes PCa cell growth and survival.Oncogene advance online publication, 2 September 2013; doi:10.1038/onc.2013.360Keywords: alternative splicing; SND1; SAM68; CD44; prostate cancer INTRODUCTION Nuclear processing of pre-mRNAs requires tightly regulated steps that ultimately yield a mature and functional mRNA. Splicing is the step that insures the removal of long non-coding sequences (introns) from the pre-mRNA and the joining of the exons. This phenomenon is driven by a large macromolecular complex, the spliceosome, composed of five small nuclear ribonucleoproteins (snRNPs) and over 200 auxiliary proteins. 1 In higher eukaryotes, a large number of exons can be alternatively spliced to yield different transcripts from a single gene, thereby increasing the coding potential of the genome. 2,3 Indeed, the large majority of multi-exon human genes undergo alternative splicing (AS) to produce at least two mRNA variants. 4,5 As regulation of AS profoundly influences physiological and pathological processes, 3,6 the full comprehension of the molecular mechanisms regulating this step of pre-mRNA processing is of fundamental importance.Splicing is physically and functionally coupled to transcription. 7-10 Two models have been proposed for how transcription might affect changes in AS patterns. The 'recruitment model' suggests that the transcription apparatus physically interacts with splicing regulators, thereby affecting splicing decisions. The C-terminal domain (CTD) of the largest subunit of the RNA polymerase II (RNAPII) has a central role in this coupling process by favoring the recruitment of RNA processing factors on the nascent transcripts. 9,10 ...

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Section: Introductionmentioning

confidence: 99%

The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

et al. 2013

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“…The GSG RNA-binding domain (aa 96 -275) of Sam68 is flanked by an N-terminal (aa 1-95) and C-terminal (aa 276 -443) regions that are known to participate to protein-protein interactions and posttranslational modifications (Lukong and Richard, 2003). Chimeric GST-Sam68(N-ter), GST-Sam68(GSG), and GST-Sam68(Cter) were produced in E. coli and purified proteins ( Figure 4C) were used as substrates for immunokinase assays in vitro.…”

Section: Erks and Mpf Isolated From Mouse Spermatocytes Directly Phosmentioning

confidence: 99%

“…Because Sam68 is phosphorylated by several kinases (Lukong and Richard, 2003), we set out to investigate if translocation of Sam68 to the cytoplasm and its association with polysomes during the meiotic divisions required phosphorylation. Sam68 was immunoprecipitated from the population enriched in secondary spermatocytes and analyzed by Western blot with different antiphospho-residue antibodies.…”

Section: Phosphorylation Of Sam68 Correlates With Cytoplasmic Localizmentioning

confidence: 99%

“…However, their precise pattern of expression and function are still largely unknown. Sam68 contains five proline-rich sequences that represent docking sites for several SH3 and WW domain-containing proteins (reviewed by Lukong and Richard, 2003). It also contains a tyrosine-rich C-terminal tail that is phosphorylated by Src-kinases in mitosis (Fumagalli et al, 1994;Taylor and Shalloway, 1994) and a nuclear localization signal embedded in this region .…”

Section: Introductionmentioning

confidence: 99%

“…STAR proteins are conserved across eukaryotes and may represent a direct link between signal transduction pathways and RNA metabolism. They bind RNA through a GSG (Grp33/Sam68/GLD-1) domain, which contains a single KH domain (hnRNP K homology domain) flanked by conserved N-and C-terminal sequences named QUA1 and QUA2 domains required for homodimerization and specificity in RNA binding (Vernet and Artzt, 1997;Lukong and Richard, 2003). Interestingly, GLD-1, a STAR protein of C. elegans, is a temporal regulator of sexual identity and it is necessary for meiotic prophase progression of germ cells (Francis et al, 1995;Jan et al, 1999;Goodwin and Ellis, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The Nuclear RNA-binding Protein Sam68 Translocates to the Cytoplasm and Associates with the Polysomes in Mouse Spermatocytes

Paronetto

Zalfa

Botti

et al. 2006

MBoC

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Translational control plays a crucial role during gametogenesis in organisms as different as worms and mammals. Mouse knockout models have highlighted the essential function of many RNA-binding proteins during spermatogenesis. Herein we have investigated the expression and function during mammalian male meiosis of Sam68, an RNA-binding protein implicated in several aspects of RNA metabolism. Sam68 expression and localization within the cells is stage specific: it is expressed in the nucleus of spermatogonia, it disappears at the onset of meiosis (leptotene/zygotene stages), and it accumulates again in the nucleus of pachytene spermatocytes and round spermatids. During the meiotic divisions, Sam68 translocates to the cytoplasm where it is found associated with the polysomes. Translocation correlates with serine/ threonine phosphorylation and it is blocked by inhibitors of the mitogen activated protein kinases ERK1/2 and of the maturation promoting factor cyclinB-cdc2 complex. Both kinases associate with Sam68 in pachytene spermatocytes and phosphorylate the regulatory regions upstream and downstream of the Sam68 RNA-binding motif. Molecular cloning of the mRNAs associated with Sam68 in mouse spermatocytes reveals a subset of genes that might be posttranscriptionally regulated by this RNA-binding protein during spermatogenesis. We also demonstrate that Sam68 shuttles between the nucleus and the cytoplasm in secondary spermatocytes, suggesting that it may promote translation of specific RNA targets during the meiotic divisions.

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The transcription factor FBI ‐1 inhibits SAM 68‐mediated BCL ‐ X alternative splicing and apoptosis

et al. 2014

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Alternative splicing (AS) is tightly coupled to transcription for the majority of human genes. However, how these two processes are linked is not well understood. Here, we unveil a direct role for the transcription factor FBI-1 in the regulation of AS. FBI-1 interacts with the splicing factor SAM68 and reduces its binding to BCL-X mRNA. This, in turn, results in the selection of the proximal 5′ splice site in BCL-X exon 2, thereby favoring the anti-apoptotic BCL-X L variant and counteracting SAM68-mediated apoptosis. Conversely, depletion of FBI-1, or expression of a SAM68 mutant lacking the FBI-1 binding region, restores the ability of SAM68 to induce BCL-X S splicing and apoptosis. FBI-1's role in splicing requires the activity of histone deacetylases, whose pharmacological inhibition recapitulates the effects of FBI-1 knockdown. Our study reveals an unexpected function for FBI-1 in splicing modulation with a direct impact on cell survival.

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Sam68, the KH domain-containing superSTAR

Cited by 191 publications

References 105 publications

The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

The Nuclear RNA-binding Protein Sam68 Translocates to the Cytoplasm and Associates with the Polysomes in Mouse Spermatocytes

The transcription factor FBI ‐1 inhibits SAM 68‐mediated BCL ‐ X alternative splicing and apoptosis

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