Patched1 functions as a gatekeeper by promoting cell cycle progression.
Mutations in the Hedgehog receptor, Patched 1 (Ptch1), have been linked to both familial and sporadic forms of basal cell carcinoma (BCC), leading to the hypothesis that loss of Ptch1 function is sufficient for tumor progression. By combining conditional knockout technology with the inducible activity of the Keratin6 promoter, we provide in vivo evidence that loss of Ptch1 function from the basal cell population of mouse skin is sufficient to induce rapid skin tumor formation, reminiscent of human BCC. Elimination of Ptch1 does not promote the nuclear translocation of beta-catenin and does not induce ectopic activation or expression of Notch pathway constituents. In the absence of Ptch1, however, a large proportion of basal cells exhibit nuclear accumulation of the cell cycle regulators cyclin D1 and B1. Collectively, our data suggest that Ptch1 likely functions as a tumor suppressor by inhibiting G1-S phase and G2-M phase cell cycle progression, and the rapid onset of tumor progression clearly indicates Ptch1 functions as a "gatekeeper." In addition, we note the high frequency and rapid onset of tumors in this mouse model makes it an ideal system for testing therapeutic strategies, such as Patched pathway inhibitors.
Adolphe
Christelle
C
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Hetherington
Rehan
R
Ellis
Tammy
T
Wainwright
Brandon
B
D000818:Animals; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D019938:Cyclin D1 / Q000378:metabolism; D018859:Hair Follicle / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism
C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D051176:beta Catenin; D019938:Cyclin D1