Constitutive activation of the shh-ptc1 pathway by a patched1 mutation identified in BCC.
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.
Barnes
Elizabeth A
EA
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.
Heidtman
Keely J
KJ
Donoghue
Daniel J
DJ
D016475:3T3 Cells; D000818:Animals; D002280:Basal Cell Carcinoma / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D053823:Hedgehog Proteins; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007668:Kidney; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D015534:Trans-Activators / Q000235:genetics*
D053823:Hedgehog Proteins; D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D015534:Trans-Activators; D006918:Hydroxyurea