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000126086 1001_ $$aRack, Paul G$$b0
000126086 245__ $$aArhgap36-dependent activation of Gli transcription factors.
000126086 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2014
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000126086 520__ $$aHedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are up-regulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.
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000126086 650_7 $$2NLM Chemicals$$aGLI1 protein, human
000126086 650_7 $$2NLM Chemicals$$aGTPase-Activating Proteins
000126086 650_7 $$2NLM Chemicals$$aGli protein, mouse
000126086 650_7 $$2NLM Chemicals$$aHedgehog Proteins
000126086 650_7 $$2NLM Chemicals$$aKruppel-Like Transcription Factors
000126086 650_7 $$2NLM Chemicals$$aNuclear Proteins
000126086 650_7 $$2NLM Chemicals$$aReceptors, G-Protein-Coupled
000126086 650_7 $$2NLM Chemicals$$aSMO protein, human
000126086 650_7 $$2NLM Chemicals$$aSmo protein, mouse
000126086 650_7 $$2NLM Chemicals$$aSmoothened Receptor
000126086 650_7 $$2NLM Chemicals$$aTranscription Factors
000126086 650_7 $$2NLM Chemicals$$aZebrafish Proteins
000126086 650_7 $$2NLM Chemicals$$aZinc Finger Protein GLI1
000126086 7001_ $$aNi, Jun$$b1
000126086 7001_ $$aPayumo, Alexander Y$$b2
000126086 7001_ $$aNguyen, Vien$$b3
000126086 7001_ $$aCrapster, J Aaron$$b4
000126086 7001_ $$0P:(DE-He78)744146d3b5a3df1e0ac555e5bf1ee5cc$$aHovestadt, Volker$$b5$$udkfz
000126086 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b6$$udkfz
000126086 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b7$$udkfz
000126086 7001_ $$aMich, John K$$b8
000126086 7001_ $$aFirestone, Ari J$$b9
000126086 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b10$$udkfz
000126086 7001_ $$aCho, Yoon-Jae$$b11
000126086 7001_ $$aChen, James K$$b12
000126086 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.1322362111$$gVol. 111, no. 30, p. 11061 - 11066$$n30$$p11061 - 11066$$tProceedings of the National Academy of Sciences of the United States of America$$v111$$x1091-6490$$y2014
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