TY - JOUR
T1 - Unique and complimentary activities of the Gli transcription factors in Hedgehog signaling
AU - Lipinski, Robert J.
AU - Gipp, Jerry J.
AU - Zhang, Jingxian
AU - Doles, Jason D.
AU - Bushman, Wade
N1 - Funding Information:
We thank Alexandra Joyner for providing Gli1 and Gli2 transgenic mice and Laura Buttitta and Chen-Ming Fan for providing GFP, Gli-GFP, Gli2-GFP, and Gli3-GFP adenoviral constructs. We also thank Dave Walterhouse, Robert Holmgren, and Aubie Shaw for critical review of the manuscript and John Fallon, Sean Hasso, Warren Heideman, and Chimera Peet for helpful suggestions. We also thank Alejandro Munoz del Rio, Norman Drinkwater, and Michael Newton for assistance with statistical analysis. This work was supported by grants from the National Institute of Health (DK 52689 and DK 56238). R.J.L. was supported by a Molecular and Environmental Toxicology Training Grant from the National Institute for Environmental Health Sciences (T32-ES07015) and J.Z. was supported in part by a grant from the Department of Defense (W81XWH-04-1-0157). Contribution 376, Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, WI 53726.
PY - 2006/7/1
Y1 - 2006/7/1
N2 - The Gli family of transcription factors (Gli1, 2 and 3) mediate the Hedgehog morphogenetic signal by regulating the expression of downstream target genes. Aberrations in Hedgehog signaling seriously affect vertebrate development. Postnatally, Hedgehog signaling has been postulated to play a pivotal role in healing and repair processes and inappropriate pathway activation has been implicated in several types of cancers. To better understand both the upstream regulation of the Gli transcription factors, as well as their unique and combinatorial roles in regulating the expression of Hedgehog target genes, we have characterized embryonic fibroblasts (MEFs) from Gli mutant mice. Stimulation of wild-type MEFs by Sonic Hedgehog (Shh) peptide elicited unique profiles of induction of Hedgehog target genes Gli1, Ptc1, and Hip1. Gli2 loss-of-function was associated with diminished Shh-induced target gene expression, while Gli3 loss-of-function was associated with increased basal and Shh-induced target gene expression. The loss of Gli1 alone had no effect on target gene induction but did diminish Shh-induced target gene expression when combined with the loss of Gli2 or Gli3. Additionally, overexpression of Gli1 induced target gene expression in Gli2-/-3-/- MEFs, while Shh stimulation did not. Using MEFs expressing only Gli2 or Gli3, we found that both cyclopamine and the PKA activator forskolin inhibited target gene induction mediated by Gli2 and Gli3. These results demonstrate that Gli2 and Gli3 share common regulatory mechanisms and modulate Hedgehog target gene expression directly and independently while also regulating Gli1 expression, which in specific contexts, coordinately contributes to target gene activation.
AB - The Gli family of transcription factors (Gli1, 2 and 3) mediate the Hedgehog morphogenetic signal by regulating the expression of downstream target genes. Aberrations in Hedgehog signaling seriously affect vertebrate development. Postnatally, Hedgehog signaling has been postulated to play a pivotal role in healing and repair processes and inappropriate pathway activation has been implicated in several types of cancers. To better understand both the upstream regulation of the Gli transcription factors, as well as their unique and combinatorial roles in regulating the expression of Hedgehog target genes, we have characterized embryonic fibroblasts (MEFs) from Gli mutant mice. Stimulation of wild-type MEFs by Sonic Hedgehog (Shh) peptide elicited unique profiles of induction of Hedgehog target genes Gli1, Ptc1, and Hip1. Gli2 loss-of-function was associated with diminished Shh-induced target gene expression, while Gli3 loss-of-function was associated with increased basal and Shh-induced target gene expression. The loss of Gli1 alone had no effect on target gene induction but did diminish Shh-induced target gene expression when combined with the loss of Gli2 or Gli3. Additionally, overexpression of Gli1 induced target gene expression in Gli2-/-3-/- MEFs, while Shh stimulation did not. Using MEFs expressing only Gli2 or Gli3, we found that both cyclopamine and the PKA activator forskolin inhibited target gene induction mediated by Gli2 and Gli3. These results demonstrate that Gli2 and Gli3 share common regulatory mechanisms and modulate Hedgehog target gene expression directly and independently while also regulating Gli1 expression, which in specific contexts, coordinately contributes to target gene activation.
KW - Gli1
KW - Gli2
KW - Gli3
KW - Mouse embryonic fibroblasts
KW - Sonic Hedgehog
KW - Transcription factors
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U2 - 10.1016/j.yexcr.2006.02.019
DO - 10.1016/j.yexcr.2006.02.019
M3 - Article
C2 - 16571352
AN - SCOPUS:33744935032
SN - 0014-4827
VL - 312
SP - 1925
EP - 1938
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 11
ER -