Journal Article

DKFZ-2017-02201

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Arhgap36-dependent activation of Gli transcription factors.

Rack, P. G. ; Ni, J. ; Payumo, A. Y. ; Nguyen, V. ; Crapster, J. A. ; Hovestadt, V.DKFZ* ; Kool, M.DKFZ* ; Jones, D.DKFZ* ; Mich, J. K. ; Firestone, A. J. ; Pfister, S.DKFZ* ; Cho, Y.-J. ; Chen, J. K.

2014
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: doi:10.1073/pnas.1322362111

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.

Keyword(s): GLI1 protein, human ; GTPase-Activating Proteins ; Gli protein, mouse ; Hedgehog Proteins ; Kruppel-Like Transcription Factors ; Nuclear Proteins ; Receptors, G-Protein-Coupled ; SMO protein, human ; Smo protein, mouse ; Smoothened Receptor ; Transcription Factors ; Zebrafish Proteins ; Zinc Finger Protein GLI1

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Contributing Institute(s):

1. Molekulare Genetik (B060)
2. Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; National-Konsortium ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection ; Zoological Record

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