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Cooperative E‐box regulation of human GLI1 by TWIST and USF
Author(s) -
Villavicencio Elisabeth H.,
Yoon Joon Won,
Frank Daniel J.,
Füchtbauer ErnstMartin,
Walterhouse David O.,
Iannaccone Philip M.
Publication year - 2002
Publication title -
genesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.093
H-Index - 110
eISSN - 1526-968X
pISSN - 1526-954X
DOI - 10.1002/gene.10078
Subject(s) - gli1 , biology , twist transcription factor , caat box , transcription factor , exon , genetics , gene , transcription (linguistics) , mutation , promoter , gene expression , nuclear protein , linguistics , philosophy
Abstract Summary: Sonic hedgehog signaling plays a critical role in vertebrate patterning, and signaling defects are associated with severe birth defects and cancer in man. GLI1 encodes a critical transcription activator in this pathway. GLI1 is expressed in human basal cell carcinomas and sarcomas. Despite the significance of the GLI1 gene in human disease, few immediate upstream regulators of GLI1 expression are known. We previously demonstrated that a 5′ region, including 5′ flanking sequence, an untranslated exon, and 425 bp of the first intron, regulates the human GLI1 gene. Here we show that inactivating mutations in E‐box, GC box, AP‐2, GATA, GSG, PuF, and Zeste sites identified three critical regulatory elements, including a GC box that binds Sp1 and two intronic E‐boxes that bind USF proteins or Twist. Expression of Twist but not a frame shift mutation of Twist activates the wild‐type human GLI1 regulatory sequences but not with inactivating mutations of the E‐boxes. Twist activates GLI1 reporter expression through E‐box +482 but requires binding of USF proteins to E‐box +157. Twist mutations cause human birth defects and Twist is overexpressed in many rhabdomyosarcomas, suggesting that one of Twist's primary roles is the regulation of GLI1 . genesis 32:247–258, 2002. © 2002 Wiley‐Liss, Inc.