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Claudio Sette - One of the best experts on this subject based on the ideXlab platform.
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The RNA-Binding Protein Sam68 is a multifunctional player in human cancer
Endocrine-related cancer, 2011Co-Authors: Pamela Bielli, Maria Paola Paronetto, Roberta Busà, Claudio SetteAbstract: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. Endocrine-Related Cancer (2011) 18 R91–R102
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the RNA Binding Protein sam68 modulates the alteRNAtive splicing of bcl x
Journal of Cell Biology, 2007Co-Authors: Maria Paola Paronetto, Tilman Achsel, Autumn Massiello, Charles E Chalfant, Claudio SetteAbstract:The RNA-Binding Protein Sam68 is involved in apoptosis, but its cellular mRNA targets and its mechanism of action remain unknown. We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alteRNAtive splicing. Depletion of Sam68 by RNA interference caused accumulation of antiapoptotic Bcl-x(L), whereas its up-regulation increased the levels of proapoptotic Bcl-x(s). Tyrosine phosphorylation of Sam68 by Fyn inverted this effect and favored the Bcl-x(L) splice site selection. A point mutation in the RNA-Binding domain of Sam68 influenced its splicing activity and subnuclear localization. Moreover, coexpression of ASF/SF2 with Sam68, or fusion with an RS domain, counteracted Sam68 splicing activity toward Bcl-x. Finally, Sam68 interacted with heterogenous nuclear RNP (hnRNP) A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated Bcl-x(s) splicing. Our results indicate that Sam68 plays a role in the regulation of Bcl-x alteRNAtive splicing and that tyrosine phosphorylation of Sam68 by Src-like kinases can switch its role from proapoptotic to antiapoptotic in live cells.
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the nuclear RNA Binding Protein sam68 translocates to the cytoplasm and associates with the polysomes in mouse spermatocytes
Molecular Biology of the Cell, 2005Co-Authors: Maria Paola Paronetto, Francesca Zalfa, Flavia Botti, Raffaele Geremia, Claudia Bagni, Claudio SetteAbstract: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.
Maria Paola Paronetto - One of the best experts on this subject based on the ideXlab platform.
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The RNA-Binding Protein Sam68 is a multifunctional player in human cancer
Endocrine-related cancer, 2011Co-Authors: Pamela Bielli, Maria Paola Paronetto, Roberta Busà, Claudio SetteAbstract: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. Endocrine-Related Cancer (2011) 18 R91–R102
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the RNA Binding Protein sam68 modulates the alteRNAtive splicing of bcl x
Journal of Cell Biology, 2007Co-Authors: Maria Paola Paronetto, Tilman Achsel, Autumn Massiello, Charles E Chalfant, Claudio SetteAbstract:The RNA-Binding Protein Sam68 is involved in apoptosis, but its cellular mRNA targets and its mechanism of action remain unknown. We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alteRNAtive splicing. Depletion of Sam68 by RNA interference caused accumulation of antiapoptotic Bcl-x(L), whereas its up-regulation increased the levels of proapoptotic Bcl-x(s). Tyrosine phosphorylation of Sam68 by Fyn inverted this effect and favored the Bcl-x(L) splice site selection. A point mutation in the RNA-Binding domain of Sam68 influenced its splicing activity and subnuclear localization. Moreover, coexpression of ASF/SF2 with Sam68, or fusion with an RS domain, counteracted Sam68 splicing activity toward Bcl-x. Finally, Sam68 interacted with heterogenous nuclear RNP (hnRNP) A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated Bcl-x(s) splicing. Our results indicate that Sam68 plays a role in the regulation of Bcl-x alteRNAtive splicing and that tyrosine phosphorylation of Sam68 by Src-like kinases can switch its role from proapoptotic to antiapoptotic in live cells.
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the nuclear RNA Binding Protein sam68 translocates to the cytoplasm and associates with the polysomes in mouse spermatocytes
Molecular Biology of the Cell, 2005Co-Authors: Maria Paola Paronetto, Francesca Zalfa, Flavia Botti, Raffaele Geremia, Claudia Bagni, Claudio SetteAbstract: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.
Myriam Gorospe - One of the best experts on this subject based on the ideXlab platform.
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lncRNA oip5 as1 cyrano sponges RNA Binding Protein hur
Nucleic Acids Research, 2016Co-Authors: Jiyoung Kim, Xiaoling Yang, Kotb Abdelmohsen, Ioannis Grammatikakis, Ji Heon Noh, Myriam GorospeAbstract:The function of the vast majority of mammalian long noncoding (lnc) RNAs remains unknown. Here, analysis of a highly abundant mammalian lncRNA, OIP5-AS1, known as cyrano in zebrafish, revealed that OIP5-AS1 reduces cell proliferation. In human cervical carcinoma HeLa cells, the RNA-Binding Protein HuR, which enhances cell proliferation, associated with OIP5-AS1 and stabilized it. Tagging OIP5-AS1 with MS2 hairpins to identify associated microRNAs revealed that miR-424 interacted with OIP5-AS1 and competed with HuR for Binding to OIP5-AS1. We further identified a 'sponge' function for OIP5-AS1, as high levels of OIP5-AS1 increased HuR-OIP5-AS1 complexes and prevented HuR interaction with target mRNAs, including those that encoded proliferative Proteins, while conversely, lowering OIP5-AS1 increased the abundance of HuR complexes with target mRNAs. We propose that OIP5-AS1 serves as a sponge or a competing endogenous (ce)RNA for HuR, restricting its availability to HuR target mRNAs and thereby repressing HuR-elicited proliferative phenotypes.
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RNA Binding Protein hur mediates cytoprotection through stimulation of xiap translation
Oncogene, 2011Co-Authors: Danielle Durie, Stephen M. Lewis, Martin Holcik, Myriam Gorospe, Urszula Liwak, M KisilewiczAbstract:Expression of the intrinsic cellular caspase inhibitor XIAP is regulated primarily at the level of Protein synthesis. The 5′ untranslated region harbours an InteRNAl Ribosome Entry Site (IRES) motif that supports cap-independent translation of XIAP mRNA during conditions of cellular stress. In this study, we show that the RNA-Binding Protein HuR, which is known to orchestrate an antiapoptotic cellular program, stimulates translation of XIAP mRNA through XIAP IRES. We further show that HuR binds to XIAP IRES in vitro and in vivo, and stimulates recruitment of the XIAP mRNA into polysomes. Importantly, protection from the apoptosis-inducing agent etoposide by overexpression of HuR requires the presence of XIAP, suggesting that HuR-mediated cytoprotection is partially executed through enhanced XIAP translation. Our data suggest that XIAP belongs to the HuR-regulated RNA operon of antiapoptotic genes, which, along with Bcl-2, Mcl-1 and ProTα, contributes to the regulation of cell survival.
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role of the RNA Binding Protein hur in colon carcinogenesis
Oncogene, 2003Co-Authors: Isabel Lopez De Silanes, Xiaoling Yang, Alan B Zonderman, Olga Potapova, Ellen S Pizer, Myriam GorospeAbstract:Immunohistochemical analysis of paired tumor and normal tissue specimens revealed that the expression and cytoplasmic abundance of the RNA-Binding Protein HuR increased with malignancy, particularly in colon carcinomas. Interventions to modulate HuR expression in human RKO colon cancer cells altered gene expression profiles and identified β-catenin mRNA as a novel HuR target. Subcutaneous injection of HuR-overexpressing RKO cells into nude mice produced significantly larger tumors than those arising from control populations; conversely, RKO cells expressing reduced HuR through small interference RNA- or antisense HuR-based approaches developed significantly more slowly. We propose that HuR-regulated target mRNA expression contributes to colon cancer growth. Our results suggest a pivotal function for HuR in colon carcinogenesis.
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RNA Binding Protein hur enhances p53 translation in response to ultraviolet light irradiation
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Krystyna Mazanmamczarz, Jennifer L. Martindale, Isabel Lopez De Silanes, Stefanie Galban, Ulus Atasoy, Jack D Keene, Myriam GorospeAbstract:Exposure to short-wavelength UV light (UVC) strongly induces p53 expression. In human RKO colorectal carcinoma cells, this increase was not due to elevated p53 mRNA abundance, cytoplasmic export of p53 mRNA, or UVC-triggered stabilization of the p53 Protein. Instead, p53 translation was potently enhanced after UVC irradiation. The 3′ UTR of p53 was found to be a target of the RNA-Binding Protein HuR in a UVC-dependent manner in vitro and in vivo. HuR-overexpressing RKO cells displayed elevated p53 levels, whereas cells expressing reduced HuR showed markedly diminished p53 abundance and p53 translation. Our results demonstrate a role for HuR in Binding to the p53 mRNA and enhancing its translation.
Xiaoling Yang - One of the best experts on this subject based on the ideXlab platform.
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lncRNA oip5 as1 cyrano sponges RNA Binding Protein hur
Nucleic Acids Research, 2016Co-Authors: Jiyoung Kim, Xiaoling Yang, Kotb Abdelmohsen, Ioannis Grammatikakis, Ji Heon Noh, Myriam GorospeAbstract:The function of the vast majority of mammalian long noncoding (lnc) RNAs remains unknown. Here, analysis of a highly abundant mammalian lncRNA, OIP5-AS1, known as cyrano in zebrafish, revealed that OIP5-AS1 reduces cell proliferation. In human cervical carcinoma HeLa cells, the RNA-Binding Protein HuR, which enhances cell proliferation, associated with OIP5-AS1 and stabilized it. Tagging OIP5-AS1 with MS2 hairpins to identify associated microRNAs revealed that miR-424 interacted with OIP5-AS1 and competed with HuR for Binding to OIP5-AS1. We further identified a 'sponge' function for OIP5-AS1, as high levels of OIP5-AS1 increased HuR-OIP5-AS1 complexes and prevented HuR interaction with target mRNAs, including those that encoded proliferative Proteins, while conversely, lowering OIP5-AS1 increased the abundance of HuR complexes with target mRNAs. We propose that OIP5-AS1 serves as a sponge or a competing endogenous (ce)RNA for HuR, restricting its availability to HuR target mRNAs and thereby repressing HuR-elicited proliferative phenotypes.
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RNA-Binding Protein HuD Controls Insulin Translation
Molecular Cell, 2012Co-Authors: Eun Kyung Lee, Wook Kim, Kumiko Tominaga, Jennifer L. Martindale, Xiaoling Yang, Sarah S. Subaran, Olga D. Carlson, Evi M. Mercken, Rohit N. Kulkarni, Wado AkamatsuAbstract:Summary Although expression of the mammalian RNA-Binding Protein HuD was considered to be restricted to neurons, we report that HuD is present in pancreatic β cells, where its levels are controlled by the insulin receptor pathway. We found that HuD associated with a 22-nucleotide segment of the 5′ untranslated region (UTR) of preproinsulin ( Ins2 ) mRNA. Modulating HuD abundance did not alter Ins2 mRNA levels, but HuD overexpression decreased Ins2 mRNA translation and insulin production, and conversely, HuD silencing enhanced Ins2 mRNA translation and insulin production. Following treatment with glucose, HuD rapidly dissociated from Ins2 mRNA and enabled insulin biosynthesis. Importantly, HuD-knockout mice displayed higher insulin levels in pancreatic islets, while HuD-overexpressing mice exhibited lower insulin levels in islets and in plasma. In sum, our results identify HuD as a pivotal regulator of insulin translation in pancreatic β cells.
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role of the RNA Binding Protein hur in colon carcinogenesis
Oncogene, 2003Co-Authors: Isabel Lopez De Silanes, Xiaoling Yang, Alan B Zonderman, Olga Potapova, Ellen S Pizer, Myriam GorospeAbstract:Immunohistochemical analysis of paired tumor and normal tissue specimens revealed that the expression and cytoplasmic abundance of the RNA-Binding Protein HuR increased with malignancy, particularly in colon carcinomas. Interventions to modulate HuR expression in human RKO colon cancer cells altered gene expression profiles and identified β-catenin mRNA as a novel HuR target. Subcutaneous injection of HuR-overexpressing RKO cells into nude mice produced significantly larger tumors than those arising from control populations; conversely, RKO cells expressing reduced HuR through small interference RNA- or antisense HuR-based approaches developed significantly more slowly. We propose that HuR-regulated target mRNA expression contributes to colon cancer growth. Our results suggest a pivotal function for HuR in colon carcinogenesis.
Joseph C Robinson - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation of importin α1 by jund modulates subcellular localization of RNA Binding Protein hur in intestinal epithelial cells
American Journal of Physiology-cell Physiology, 2016Co-Authors: Jie Chen, Lan Xiao, Hee Kyoung Chung, Yuan Zhang, Joseph C RobinsonAbstract:The RNA-Binding Protein HuR is crucial for normal intestinal mucosal regeneration by modulating the stability and translation of target mRNAs, but the exact mechanism underlying HuR trafficking bet...
