肿瘤坏死因子 α（TNFalpha）通过 SMAR1 磷酸化调节 CD40 表达。

Tumor Necrosis Factor alpha (TNFalpha) regulates CD40 expression through SMAR1 phosphorylation.

机构信息

National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411 007, Maharashtra, India.

出版信息

Biochem Biophys Res Commun. 2010 Jan 8;391(2):1255-61. doi: 10.1016/j.bbrc.2009.12.055. Epub 2009 Dec 16.

DOI:10.1016/j.bbrc.2009.12.055

PMID:20006573

Abstract

CD40 plays an important role in mediating inflammatory response and is mainly induced by JAK/STAT phosphorylation cascade. TNFalpha is the key cytokine that activates CD40 during inflammation and tumorigenesis. We have earlier shown that SMAR1 can repress the transcription of Cyclin D1 promoter by forming a HDAC1 dependent repressor complex. In this study, we show that SMAR1 regulates the transcription of NF-kappaB target gene CD40. SMAR1 recruits HDAC1 and forms a repressor complex on CD40 promoter and keeps its basal transcription in check. Further, we show that TNFalpha stimulation induces SMAR1 phosphorylation at Ser-347 and promotes its cytoplasmic translocation, thus releasing its negative effect. Concomitantly, TNFalpha induced phosphorylation of STAT1 at Tyr-701 by JAK1 facilitates its nuclear translocation and activation of CD40 through p300 recruitment and core Histone-3 acetylation. Thus, TNFalpha mediated regulation of CD40 expression occurs by dual phosphorylation of SMAR1 and STAT1.

摘要

CD40 在介导炎症反应中起着重要作用，主要通过 JAK/STAT 磷酸化级联诱导。TNFalpha 是炎症和肿瘤发生过程中激活 CD40 的关键细胞因子。我们之前已经表明，SMAR1 可以通过形成依赖于 HDAC1 的抑制复合物来抑制 Cyclin D1 启动子的转录。在这项研究中，我们表明 SMAR1 调节 NF-κB 靶基因 CD40 的转录。SMAR1 募集 HDAC1 并在 CD40 启动子上形成抑制复合物，以控制其基础转录。此外，我们表明 TNFalpha 刺激诱导 SMAR1 在 Ser-347 处发生磷酸化，并促进其细胞质易位，从而释放其负效应。同时，TNFalpha 通过 JAK1 诱导 STAT1 在 Tyr-701 处发生磷酸化，促进其核易位，并通过募集 p300 和核心组蛋白 H3 乙酰化来激活 CD40。因此，TNFalpha 通过 SMAR1 和 STAT1 的双重磷酸化来调节 CD40 的表达。