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The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation

Oncogene volume 26, pages 1122–1136 (2007)Cite this article

Abstract

The mechanism by which activation of the Hedgehog (Hh) pathway modulates differentiation and promotes oncogenesis in specific tissues is poorly understood. We therefore, analysed rhabdomyosarcomas from mice that were haploinsufficient for the Hh-binding protein, Hip1, or for the Hh receptor, Patched 1 (Ptch1). Transfection of the Hh-regulated transcription factor Gli1, which is expressed in a subset of mouse and human rhabdomyosarcomas, suppressed differentiation of myogenic rhabdomyosarcoma lines generated from Hip1+/− and Ptch1+/− mice. The closely related factor, Gli2, had similar effects. Gli1 and Gli2 inhibited myogenesis by repressing the capacity of MyoD to activate transcription. Deletion analysis of Gli1 indicated that multiple domains of Gli1 are required for efficient inhibition of MyoD. Gli1 reduced the ability of MyoD to heterodimerize with E12 and bind DNA, providing one mechanism whereby the Gli proteins modulate the activity of MyoD. This novel activity of Gli proteins provides new insights into how Hh signaling modulates terminal differentiation through inhibition of tissue-specific factors such as MyoD. This mechanism may contribute to the broad role of Hh signaling and the Gli proteins in differentiation decisions and cancer formation.

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Acknowledgements

We are indebted to those who provided plasmids and cell lines that we used for this work, including Stephen Tapscott, Steven Swoap, Brian Black, Hiroshi Sasaki, Bert Vogelstein, Robert Hill, Kenneth Baldwin, Miao-Hsueh Chen and Hisato Kondoh. We thank Stephen Tapscott, Brian Black, and Analeah Heidt for helpful discussion and Nicholas Gerber, Brian Black, Matthias Hebrok, Zena Werb, and Analeah Heidt for critical reading of the manuscript. This work was supported by NIH grant HL067822, NHLBI-funded Program for Genomics Applications (“BayGenomics”) HL66600; and NIH grant K08HL07715 and a Parker B. Francis Fellowship (A.N.G).

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  1. Cardiovascular Research Institute, University of California, San Francisco, CA, USA

    A N Gerber, C W Wilson, Y-J Li & P-T Chuang

  2. Department of Medicine, University of California, San Francisco, CA, USA

    A N Gerber

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Correspondence to P-T Chuang.

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Gerber, A., Wilson, C., Li, YJ. et al. The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation. Oncogene 26, 1122–1136 (2007). https://doi.org/10.1038/sj.onc.1209891

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