Hierarchical model of gene regulation by transforming growth factor β

被引:178
作者
Yang, YC
Piek, E
Zavadil, J
Liang, D
Xie, DL
Heyer, J
Pavlidis, P
Kucherlapati, R
Roberts, AB
Böttinger, EP
机构
[1] Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
[2] Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA
[3] NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA
[4] Columbia Univ, Columbia Genome Ctr, New York, NY 10032 USA
关键词
D O I
10.1073/pnas.1834070100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Transforming growth factor betas (TGF-betas) regulate key aspects of embryonic development and major human diseases. Although Smad2, Smad3, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs) have been proposed as key mediators in TGF-beta signaling, their functional specificities and interactivity in controlling transcriptional programs in different cell types and (patho)physiological contexts are not known. We investigated expression profiles of genes controlled by TGF-beta in fibroblasts with ablations of Smad2, Smad3, and ERK MAPK. Our results suggest that Smad3 is the essential mediator of TGF-beta signaling and directly activates genes encoding regulators of transcription and signal transducers through Smad3/Smad4 DNA-binding motif repeats that are characteristic for immediate-early target genes of TGF-beta but absent in intermediate target genes. In contrast, Smad2 and ERK predominantly transmodulated regulation of both immediate-early and intermediate genes by TGF-beta/Smad3. These results suggest a previously uncharacterized hierarchical model of gene regulation by TGF-beta in which TGF-beta causes direct activation by Smad3 of cascades of regulators of transcription and signaling that are transmodulated by Smad2 and/or ERK.
引用
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页码:10269 / 10274
页数:6
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