The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome.
Mutations in the transmembrane receptor patched homolog 1 (Homo sapiens) (ptch1) are responsible for nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder that causes developmental abnormalities and predisposes the affected individuals to cancer. Many of these mutations, including mutations in the C-terminus of the large intracellular loop (ICL) of ptch1 (p.C727VfsX745 and p.S733IfsX736), result in the premature truncation of the protein. The ptch1‑C727VfsX745 and ptch1-S733IfsX736 mutations have been identified in patients with NBCCS‑associated keratocystic odontogenic tumors (KCOTs). In the present study, we found that the molecular mechanisms regulated by the non-canonical Hedgehog (Hh) signaling pathway through cyclin B1 are involved in the pathogenesis of NBCCS-associated KCOTs. In contrast to wild-type ptch1, ptch1-C727VfsX745 and ptch1‑S733IfsX736 clearly exhibited reduced binding to cyclin B1. Moreover, the cells expressing these two mutations demonstrated an increase in cell cycle progression and these two mutation constructs failed to inhibit cell proliferation. In addition, the mutants enhanced the activity of glioma-associated oncogene family zinc finger 1 (GLI1), a downstream reporter of Hh signaling. Thus, our data suggest that the non-canonical Hh pathway mediated through ptch1 and cyclin B1 is involved in the pathogenesis of NBCCS-associated KCOTs. The C-terminus of ICL in ptch1 may also be a potential therapeutic target in the treatment of this disease.
Department of Oral Pathology, Peking University School and Hospital of Stomatology, Haidian District, Beijing 100081, P.R. China.
Fei-Yan
FY
Yu
Department of Oral Pathology, Peking University School and Hospital of Stomatology, Haidian District, Beijing 100081, P.R. China.
Ying-Ying
YY
Hong
Department of Oral Pathology, Peking University School and Hospital of Stomatology, Haidian District, Beijing 100081, P.R. China.
Jia-Fei
JF
Qu
Central Laboratory, Peking University School and Hospital of Stomatology, Haidian District, Beijing 100081, P.R. China.
Feng
F
Chen
Department of Oral Pathology, Peking University School and Hospital of Stomatology, Haidian District, Beijing 100081, P.R. China.
Tie-Jun
TJ
Li
D000818:Animals; D001478:Basal Cell Nevus Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D051527:Odontogenic Tumor, Squamous / Q000235:genetics* / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
D056744:Cyclin B1; C400551:GLI1 protein, human; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1