Investigation of the Regulatory Effect of ZRF1 on S100A8 and S100A9 Protein Levels Under Inflammatory Conditions in a THP-1 Macrophage Model

Project no. 33299 · Status: Kapanmış · 2025

Summary

<p>ZRF1&nbsp;(Zuotin-Related&nbsp;Factor&nbsp;1)&nbsp;is&nbsp;a&nbsp;chromatin-associated&nbsp;protein&nbsp;involved&nbsp;in&nbsp;the&nbsp;epigenetic&nbsp;regulation&nbsp;of&nbsp;gene&nbsp;expression&nbsp;and&nbsp;has&nbsp;been&nbsp;implicated&nbsp;in&nbsp;diverse&nbsp;biological&nbsp;processes,&nbsp;including&nbsp;cellular&nbsp;differentiation,&nbsp;stress&nbsp;responses,&nbsp;and&nbsp;tumor&nbsp;progression.&nbsp;RNA&nbsp;sequencing&nbsp;analyses&nbsp;performed&nbsp;in&nbsp;our&nbsp;laboratory&nbsp;using&nbsp;breast&nbsp;cancer&nbsp;cells&nbsp;demonstrated&nbsp;that&nbsp;ZRF1&nbsp;silencing&nbsp;resulted&nbsp;in&nbsp;a&nbsp;29-fold&nbsp;and&nbsp;36-fold&nbsp;increase&nbsp;in&nbsp;the&nbsp;expression&nbsp;of&nbsp;S100A8&nbsp;and&nbsp;S100A9,&nbsp;respectively.&nbsp;These&nbsp;findings&nbsp;suggest&nbsp;that&nbsp;ZRF1&nbsp;may&nbsp;function&nbsp;as&nbsp;a&nbsp;transcriptional&nbsp;repressor&nbsp;of&nbsp;the&nbsp;S100&nbsp;protein&nbsp;family&nbsp;and&nbsp;play&nbsp;a&nbsp;regulatory&nbsp;role&nbsp;in&nbsp;the&nbsp;expression&nbsp;of&nbsp;inflammation-associated&nbsp;genes.</p><p></p><p>S100A8&nbsp;and&nbsp;S100A9&nbsp;are&nbsp;calcium-binding&nbsp;alarmin&nbsp;proteins&nbsp;that&nbsp;are&nbsp;physiologically&nbsp;expressed&nbsp;at&nbsp;high&nbsp;levels&nbsp;in&nbsp;neutrophils,&nbsp;monocytes,&nbsp;and&nbsp;macrophages.&nbsp;In&nbsp;the&nbsp;extracellular&nbsp;environment,&nbsp;they&nbsp;function&nbsp;as&nbsp;damage-associated&nbsp;molecular&nbsp;patterns&nbsp;(DAMPs)&nbsp;and&nbsp;activate&nbsp;key&nbsp;signaling&nbsp;pathways,&nbsp;including&nbsp;NF-κB&nbsp;and&nbsp;mTOR,&nbsp;through&nbsp;TLR4&nbsp;and&nbsp;RAGE&nbsp;receptors.&nbsp;Through&nbsp;these&nbsp;mechanisms,&nbsp;they&nbsp;promote&nbsp;the&nbsp;production&nbsp;of&nbsp;pro-inflammatory&nbsp;cytokines,&nbsp;facilitate&nbsp;immune&nbsp;cell&nbsp;recruitment,&nbsp;and&nbsp;contribute&nbsp;to&nbsp;the&nbsp;establishment&nbsp;of&nbsp;an&nbsp;inflammatory&nbsp;microenvironment.&nbsp;Sustained&nbsp;upregulation&nbsp;of&nbsp;S100A8&nbsp;and&nbsp;S100A9&nbsp;plays&nbsp;a&nbsp;critical&nbsp;role&nbsp;in&nbsp;chronic&nbsp;inflammation&nbsp;and&nbsp;the&nbsp;disruption&nbsp;of&nbsp;tissue&nbsp;homeostasis.&nbsp;However,&nbsp;the&nbsp;transcriptional&nbsp;mechanisms&nbsp;governing&nbsp;their&nbsp;expression,&nbsp;particularly&nbsp;the&nbsp;regulation&nbsp;of&nbsp;their&nbsp;protein&nbsp;levels,&nbsp;remain&nbsp;poorly&nbsp;understood.</p><p></p><p>Building&nbsp;on&nbsp;our&nbsp;previous&nbsp;findings,&nbsp;this&nbsp;project&nbsp;aims&nbsp;to&nbsp;systematically&nbsp;investigate&nbsp;the&nbsp;changes&nbsp;in&nbsp;the&nbsp;intracellular&nbsp;and&nbsp;extracellular&nbsp;protein&nbsp;levels&nbsp;of&nbsp;S100A8&nbsp;and&nbsp;S100A9&nbsp;under&nbsp;inflammatory&nbsp;conditions&nbsp;in&nbsp;the&nbsp;absence&nbsp;of&nbsp;ZRF1.&nbsp;In&nbsp;addition,&nbsp;the&nbsp;dynamic&nbsp;redistribution&nbsp;of&nbsp;ZRF1&nbsp;between&nbsp;the&nbsp;nuclear&nbsp;and&nbsp;cytoplasmic&nbsp;compartments&nbsp;in&nbsp;response&nbsp;to&nbsp;inflammatory&nbsp;stimulation&nbsp;will&nbsp;be&nbsp;examined&nbsp;using&nbsp;subcellular&nbsp;fractionation.&nbsp;By&nbsp;addressing&nbsp;these&nbsp;objectives,&nbsp;the&nbsp;project&nbsp;seeks&nbsp;to&nbsp;fill&nbsp;an&nbsp;important&nbsp;gap&nbsp;in&nbsp;our&nbsp;understanding&nbsp;of&nbsp;the&nbsp;epigenetic&nbsp;role&nbsp;of&nbsp;ZRF1&nbsp;in&nbsp;inflammation&nbsp;and&nbsp;alarmin&nbsp;regulation&nbsp;and&nbsp;to&nbsp;provide&nbsp;novel&nbsp;insights&nbsp;into&nbsp;the&nbsp;epigenetic&nbsp;mechanisms&nbsp;underlying&nbsp;immune&nbsp;responses.</p><p></p><p></p>

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