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Constitutive activation of the shh–ptc1 pathway by a patched1 mutation identified in BCC

Oncogene volume 24, pages 902–915 (2005)Cite this article

Abstract

Mutations in the transmembrane receptor patched1 (ptc1) are responsible for the majority of basal cell carcinoma (BCC) cases. Many of these mutations, including ptc1-Q688X, result in premature truncation of the ptc1 protein. ptc1-Q688X has been identified in patients with both BCC and nevoid basal cell carcinoma syndrome, an inheritable disorder causing a predisposition to cancer susceptibility. Here we describe a mechanism by which ptc1-Q688X causes constitutive cellular signaling. Cells expressing ptc1-Q688X demonstrate an increase in cell cycle progression and induce cell transformation. The ptc1-Q688X mutant enhances Gli1 activity, a downstream reporter of sonic hedgehog (shh)–ptc1 signaling, independent of shh stimulation. In contrast to wild-type ptc1, ptc1-Q688X fails to associate with endogenous cyclin B1. Expression of nuclear-targeted cyclin B1 derivatives promotes Gli1-dependent transcription, which correlates temporally with cyclin B1–cdk1 kinase activity. Coexpression of wild-type ptc1 with a nuclear-targeted cyclin B1 derivative, mutated to mimic constitutive phosphorylation, dramatically decreases Gli1 activity. In addition, the coexpression of this constitutively nuclear cyclin B1 derivative with ptc1-Q688X substantially enhances foci formation. These studies therefore describe a molecular mechanism for the aberrant activity of ptc1-Q688X that includes the premature activation of the transcription factor Gli1.

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Acknowledgements

We thank Genentech Inc. for providing the Gli1-luciferase reporter construct, J Ming and MP Scott for providing the Myc-tagged ptc1 construct, AN Meyer and members of the Donoghue lab for critical review of the manuscript and LJ Castrejon for editorial assistance. This work was supported by NIH Grant T32-CA09523 and NIH Grant GM65490. DNA sequencing was performed by the UCSD Cancer Center, DNA Sequencing Shared Resource, funded in part by NCI Cancer Center Support Grant #2 P30 CA23100-18.

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  1. Department of Chemistry and Biochemistry, Center for Molecular Genetics, University of California, 9500 Gilman Drive, Urey Hall-6114, San Diego, La Jolla, CA, 92093-0367, USA

    Elizabeth A Barnes, Keely J Heidtman & Daniel J Donoghue

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  1. Elizabeth A Barnes
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Correspondence to Daniel J Donoghue.

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Barnes, E., Heidtman, K. & Donoghue, D. Constitutive activation of the shh–ptc1 pathway by a patched1 mutation identified in BCC. Oncogene 24, 902–915 (2005). https://doi.org/10.1038/sj.onc.1208240

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