Arhgap36-dependent activation of Gli transcription factors

Paul G. Rack, Jun Ni, Alexander Y. Payumo, Vien Nguyen, J. Aaron Crapster, Volker Hovestadt, Marcel Kool, David T.W. Jones, John K. Mich, Ari J. Firestone, Stefan M. Pfister, Yoon-Jae Cho, James K. Chen

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 upregulated 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.

Original languageEnglish (US)
Pages (from-to)11061-11066
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number30
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Medulloblastoma
Transcription Factors
Kinesin
Aptitude
Cilia
Transcriptional Activation
Carrier Proteins
Protein Isoforms
Carcinogenesis
Homeostasis
Complementary DNA
Genome
Neoplasms
Proteins
Zinc Finger Protein GLI1
In Vitro Techniques

ASJC Scopus subject areas

  • General

Cite this

Rack, P. G., Ni, J., Payumo, A. Y., Nguyen, V., Crapster, J. A., Hovestadt, V., ... Chen, J. K. (2014). Arhgap36-dependent activation of Gli transcription factors. Proceedings of the National Academy of Sciences of the United States of America, 111(30), 11061-11066. https://doi.org/10.1073/pnas.1322362111

Arhgap36-dependent activation of Gli transcription factors. / Rack, Paul G.; Ni, Jun; Payumo, Alexander Y.; Nguyen, Vien; Crapster, J. Aaron; Hovestadt, Volker; Kool, Marcel; Jones, David T.W.; Mich, John K.; Firestone, Ari J.; Pfister, Stefan M.; Cho, Yoon-Jae; Chen, James K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 30, 01.01.2014, p. 11061-11066.

Research output: Contribution to journalArticle

Rack, PG, Ni, J, Payumo, AY, Nguyen, V, Crapster, JA, Hovestadt, V, Kool, M, Jones, DTW, Mich, JK, Firestone, AJ, Pfister, SM, Cho, Y-J & Chen, JK 2014, 'Arhgap36-dependent activation of Gli transcription factors', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 30, pp. 11061-11066. https://doi.org/10.1073/pnas.1322362111
Rack, Paul G. ; Ni, Jun ; Payumo, Alexander Y. ; Nguyen, Vien ; Crapster, J. Aaron ; Hovestadt, Volker ; Kool, Marcel ; Jones, David T.W. ; Mich, John K. ; Firestone, Ari J. ; Pfister, Stefan M. ; Cho, Yoon-Jae ; Chen, James K. / Arhgap36-dependent activation of Gli transcription factors. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 30. pp. 11061-11066.
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