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首页> 外文学位 >Identification and functional characterization of HSH2, a dynamically expressed adaptor protein implicated in B cell survival signaling.
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Identification and functional characterization of HSH2, a dynamically expressed adaptor protein implicated in B cell survival signaling.

机译：HSH2的鉴定和功能表征，HSH2是一种动态表达的衔接蛋白，涉及B细胞存活信号传导。

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摘要

HSH2 was identified in a bioinformatics-based search for novel adaptor proteins that are preferentially expressed in B lymphocytes. Interaction of hematopoietic Src homology 2 (HSH2) with the anti-apoptotic BCL-2 family protein Hax-1 implicated HSH2 in regulation of apoptosis. Expression of HSH2 in the WEHI-231 immature B cell line by retroviral transduction attenuates antigen receptor-induced apoptosis by preventing mitochondrial membrane depolarization. Furthermore, endogenous HSH2 expression is diminished by pro-apoptotic antigen receptor stimulation. In contrast, pro-survival signaling through CD40 up-regulates HSH2 expression and prevents antigen receptor-mediated down-regulation of HSH2. HSH2 expression is also up-regulated by anti-CD40, lipopoly-saccharide (LPS), CpG DNA, and BlyS stimulation of murine splenic B cells. Anti-CD40, LPS, and CpG DNA activate numerous B cell processes; including differentiation, proliferation, and survival; BlyS primarily regulates B cell homeostasis and survival and does not induce proliferation or plasma cell differentiation. All of these stimuli promote B cell survival by up-regulation of anti-apoptotic molecules through NF-kappaB activation. Treatment of splenic B cells with inhibitors of NF-kappaB activation prevented up-regulation of HSH2 by anti-CD40, LPS, CpG DNA, and BlyS, suggesting HSH2 expression is NF-kappaB dependent. HSH2 expression is also diminished by apoptosis-inducing stimulation by Interleukin (IL)-21. IL-2l stimulation induces apoptosis of anti-CD40-, LPS-, and CpG DNA-treated splenic B cells by down-regulating anti-apoptotic molecules such as Bcl-xL and up-regulating pro-apoptotic proteins like Bim that potentiate mitochondrial membrane depolarization. Therefore, HSH2 expression is coordinately regulated with known anti-apoptotic molecules under conditions that promote B cell survival. These data suggest that HSH2 is a component of a pro-survival signaling module that functions to prevent B cell apoptosis by maintaining mitochondrial membrane stability.
机译：HSH2在基于生物信息学的搜索中找到了优先在B淋巴细胞中表达的新型衔接子蛋白。造血Src同源性2（HSH2）与抗凋亡的BCL-2家族蛋白Hax-1的相互作用牵涉HSH2调控细胞凋亡。 HSH2在WEHI-231未成熟B细胞系中的表达通过逆转录病毒转导通过防止线粒体膜去极化来减弱抗原受体诱导的凋亡。此外，促凋亡抗原受体刺激减少了内源性HSH2表达。相反，通过CD40进行的生存信号转导可以上调HSH2的表达并防止抗原受体介导的HSH2的下调。小鼠脾脏B细胞的抗CD40，脂多糖（LPS），CpG DNA和BlyS刺激还可以上调HSH2表达。抗CD40，LPS和CpG DNA可以激活许多B细胞过程。包括分化，增殖和生存； BlyS主要调节B细胞的稳态和存活，不诱导增殖或浆细胞分化。所有这些刺激都通过NF-κB激活上调抗凋亡分子来促进B细胞存活。用NF-kappaB激活抑制剂处理脾脏B细胞可防止抗CD40，LPS，CpG DNA和BlyS对HSH2的上调，表明HSH2表达是NF-kappaB依赖性的。通过白介素（IL）-21的细胞凋亡诱导刺激，HSH2表达也减少。 IL-21刺激通过下调抗凋亡分子（如Bcl-xL）和上调促凋亡蛋白（如Bim）来增强线粒体膜，从而诱导抗CD40，LPS和CpG DNA处理的脾B细胞凋亡。去极化。因此，在促进B细胞存活的条件下，HSH2的表达受到已知的抗凋亡分子的协调调节。这些数据表明，HSH2是促生存信号模块的一部分，其通过维持线粒体膜的稳定性来防止B细胞凋亡。

著录项

  • 作者

    Herrin, Brantley R.;

  • 作者单位

    The University of Alabama at Birmingham.;

  • 授予单位 The University of Alabama at Birmingham.;
  • 学科 Immunology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 99 p.
  • 总页数 99
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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