The Sam68 STAR RNA-Binding Protein Regulates mTOR Alternative Splicing during Adipogenesis

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• 作者：Marc-É ; tienne Huot¹ ; ² ; ³ ; ⁴ ; Gillian Vogel¹ ; ² ; ³ ; Amber Zabarauskas¹ ; ² ; ³ ; Chau  ; Tuan-Anh Ngo¹ ; ² ; ³ ; Jasmin Coulombe-Huntington⁵ ; Jacek Majewski⁵ ; Sté ; phane Richard¹ ; ² ; ³ ; ^{stephane.richard@mcgill.ca}
• 刊名：Molecular Cell
• 出版年：2012
• 期刊代码：111_10972765
• 类别：bio
• 出版时间：27 April, 2012
• 卷：46
• 期：2
• 页码：187-199
• 文件大小：1519 K

摘要

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Summary

We report that mice ablated for the Sam68 RNA-binding protein exhibit a lean phenotype as a result of increased energy expenditure, decreased commitment to early adipocyte progenitors, and defects in adipogenic differentiation. The m>Sam68m>^{鈭?鈭?/sup> mice were protected from obesity, insulin resistance, and glucose intolerance induced with a high-fat diet. To identify the alternative splice events regulated by Sam68, genome-wide exon usage profiling in white adipose tissue was performed. Adipocytes from m>Sam68m>鈭?鈭?/sup> mice retained intron 5 within the mTOR transcript introducing a premature termination codon, leading to an unstable mRNA. Consequently, Sam68-depleted cells had reduced mTOR levels resulting in lower levels of insulin-stimulated S6 and Akt phosphorylation leading to defects in adipogenesis, and this defect was rescued by the exogenous expression of full-length mTOR. Sam68 bound intronic splice elements within mTOR intron 5 required for the usage of the 5鈥?splice site. We propose that Sam68 regulates alternative splicing during adipogenesis.}