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Post-transcriptional regulation of mRNA metabolism during differentiation of 3T3-L1 cells: Role of HuR.

机译：3T3-L1细胞分化过程中mRNA代谢的转录后调节：HuR的作用。

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摘要

Our studies address early control points in the differentiation process that are necessary for expression as well as the maintenance of the adipocyte phenotype. We have focused on the post-transcriptional regulation of mRNA metabolism by the RNA binding protein HuR. Depending on the particular mRNA, HuR has been suggested to control polyadenylation, translocation to the cytosol, mRNA stability, and/or translational efficiency. Using the 3T3-L1 preadipocyte cell line, we have demonstrated a critical role for HuR in the differentiation process by use of siRNA mediated suppression which resulted in an inhibition of differentiation. We have identified several mRNAs that serve as HuR ligands early in the differentiation process, one of which is C/EBPbeta, an important adipocyte transcription factor, whose expression is highly controlled and essential for proper acquisition of the adipocyte phenotype. Within minutes of induction of differentiation, HuR forms an mRNP complex with C/EBPbeta mRNA in the nucleus followed by translocation to the cytoplasm. HuR remains associated with C/EBPbeta mRNA suggesting a role in mRNA stability and translation efficiency. Our data suggest that formation of this complex in the nucleus serves as a regulator/attenuator of polyadenylation and that this interaction leads to a controlled metabolism of the C/EBPbeta mRNA by determination of the quantity of message translocated to the cytosol and available for translation. Additionally, our data have directed us toward the Zfp206 mRNA as an important HuR ligand whose regulation is predicted to be responsible for maintenance of the differentiation potential of the cells and whose expression is terminated as the cells express PPARgamma and establish the adipocyte phenotype. Our mechanistic analysis of these issues will identify novel control points in the initial stages of adipogenesis and thus fundamental to the pathological states of obesity and diabetes.
机译：我们的研究解决了分化过程中表达和维持脂肪细胞表型所必需的早期控制点。我们已经集中在RNA结合蛋白HuR对mRNA代谢的转录后调控上。根据特定的mRNA，已建议HuR控制聚腺苷酸化，向细胞质的易位，mRNA稳定性和/或翻译效率。使用3T3-L1前脂肪细胞系，我们已证明通过使用siRNA介导的抑制作用（导致分化抑制），HuR在分化过程中起着关键作用。我们已经鉴定了几种在分化过程中早期充当HuR配体的mRNA，其中之一是C / EBPbeta，这是一种重要的脂肪细胞转录因子，其表达受到高度控制，对于正确获取脂肪细胞表型至关重要。在诱导分化的几分钟内，HuR在细胞核中与C / EBPbeta mRNA形成了mRNP复合物，然后易位至细胞质。 HuR仍然与C / EBPbeta mRNA相关，表明在mRNA稳定性和翻译效率中起作用。我们的数据表明，这种复合物在细胞核中的形成可作为聚腺苷酸化的调节剂/减毒剂，并且这种相互作用通过确定易位到细胞质中且可翻译的信息量，导致C / EBPbeta mRNA的受控代谢。此外，我们的数据已将Zfp206 mRNA定位为重要的HuR配体，据预测其调控作用可维持细胞的分化潜能，并且随着细胞表达PPARγ并建立脂肪细胞表型，其表达终止。我们对这些问题的机理分析将在脂肪形成的初始阶段确定新的控制点，从而成为肥胖症和糖尿病病理状态的基础。

著录项

  • 作者

    Karschner, Vesna Ann.;

  • 作者单位

    East Carolina University.;

  • 授予单位 East Carolina University.;
  • 学科 Biology Microbiology.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 157 p.
  • 总页数 157
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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