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Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):11061-6. doi: 10.1073/pnas.1322362111. Epub 2014 Jul 14.

Arhgap36-dependent activation of Gli transcription factors.

Author information

1
Departments of Chemical and Systems Biology.
2
Departments of Pediatrics andNeurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regenerative Medicine, University of California, San Francisco, CA 94143;
3
Divisions of Molecular Genetics and.
4
Pediatric Neurooncology, German Cancer Research Center, 69120 Heidelberg, Germany; and.
5
Biochemistry, Stanford University School of Medicine, Stanford, CA 94305;
6
Pediatric Neurooncology, German Cancer Research Center, 69120 Heidelberg, Germany; andDepartment of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
7
Neurology and Neurological Sciences,Neurosurgery.
8
Departments of Chemical and Systems Biology,Developmental Biology, and jameschen@stanford.edu.

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.

PMID:
25024229
PMCID:
PMC4121843
DOI:
10.1073/pnas.1322362111
[Indexed for MEDLINE]
Free PMC Article

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