ZFIN ID: ZDB-PUB-170214-310
Arhgap36-dependent activation of Gli transcription factors
Rack, P.G., Ni, J., Payumo, A.Y., Nguyen, V., Crapster, J.A., Hovestadt, V., Kool, M., Jones, D.T., Mich, J.K., Firestone, A.J., Pfister, S.M., Cho, Y.J., Chen, J.K.
Date: 2014
Source: Proceedings of the National Academy of Sciences of the United States of America   111: 11061-6 (Journal)
Registered Authors: Chen, James K., Firestone, Ari, Mich, John, Rack, Paul
Keywords: none
MeSH Terms:
  • Animals
  • Cilia/genetics
  • Cilia/metabolism
  • GTPase-Activating Proteins/genetics
  • GTPase-Activating Proteins/metabolism*
  • Gene Expression Profiling
  • Hedgehog Proteins/genetics
  • Hedgehog Proteins/metabolism
  • Humans
  • Kruppel-Like Transcription Factors/genetics
  • Kruppel-Like Transcription Factors/metabolism*
  • Medulloblastoma/genetics
  • Medulloblastoma/metabolism*
  • Medulloblastoma/pathology
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Nuclear Proteins/genetics
  • Nuclear Proteins/metabolism*
  • Receptors, G-Protein-Coupled/genetics
  • Receptors, G-Protein-Coupled/metabolism
  • Smoothened Receptor
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Zinc Finger Protein GLI1
PubMed: 25024229 Full text @ Proc. Natl. Acad. Sci. USA
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ABSTRACT
Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are up-regulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.
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