Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor

Cai  WJ; He  JC; Zhu  LLu  CYVlassara  H

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Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor

机译：Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor

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Advanced glycation end product receptors (AGERs) play distinct functional roles in both the toxicity and disposal of advanced glycation end products (AGEs), substances that are linked to diabetes and aging. Overexpression of AGER1 in murine mesangial cells (MCs) (MC-R1) inhibited AGE-induced MAPK1,2 phosphorylation and NF-kappa B activity and also increased AGE degradation. The mechanism of the inhibitory effects of AGER1, upstream of MAPK, was explored in MCs and HEK293 AGER1-expressing cells. AGE-induced Ras activation was found to be linked to Shc/Grb2 complex formation and Shc phosphorylation in MCs, responses that were markedly reduced in MC-R1 cells. AGE responses also included EGF receptor (EGFR) phosphorylation in MCs or HEK293 cells, but this link was blocked in both MC-R1 and HEK293-R1 cells. Coexpression of AGER1 and EGFR in HEK293 cells decreased AGE-mediated EGFR and p44/p42 phosphorylation but not EGF-induced p44/p42 activation. AGE, S100/calgranulin, or H2O2 promoted MAPK phosphorylation in EGFR(+) cells in a manner that was inhibitable by an EGFR inhibitor, AG1478. Also, in AGER1 cells, AGE-induced H2O2 formation and AGE- or S100-induced p44/p42 phosphorylation were suppressed, and these effects were restored by R1 siRNA. These data confirm that RI negatively regulates AGE-mediated oxidant stress-dependent signaling via the EGFR and Shc/Grb2/Ras pathway. AGER1 could serve as a model for developing therapeutic targets against vascular and kidney disorders related to diabetes and aging.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2006年第37期|13801-13806|共6页
作者
Cai WJ; He JC; Zhu LLu CYVlassara H;
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作者单位

Mt Sinai Sch Med, Div Expt Diabet & Aging, Brookdale Dept Geriatr, New York, NY 10029 USA;

Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
phosphorylation; reactive oxygen species; mesangial cells; MAPK; diabetes; EPIDERMAL-GROWTH-FACTOR; PROTEIN-KINASE PATHWAY; OXIDATIVE STRESS; TYROSINE KINASE; DIABETIC COMPLICATIONS; VASCULAR DYSFUNCTION; BINDING DOMAIN; RENAL-DISEASE; INTACT-CELLS; RAS;

Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor

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