The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome

  • Authors:
    • Fei-Yan Yu
    • Ying-Ying Hong
    • Jia-Fei Qu
    • Feng Chen
    • Tie-Jun Li
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  • Published online on: May 16, 2014     https://doi.org/10.3892/ijmm.2014.1783
  • Pages: 507-512
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Abstract

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.
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August-2014
Volume 34 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Yu F, Hong Y, Qu J, Chen F and Li T: The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome. Int J Mol Med 34: 507-512, 2014.
APA
Yu, F., Hong, Y., Qu, J., Chen, F., & Li, T. (2014). The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome. International Journal of Molecular Medicine, 34, 507-512. https://doi.org/10.3892/ijmm.2014.1783
MLA
Yu, F., Hong, Y., Qu, J., Chen, F., Li, T."The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome". International Journal of Molecular Medicine 34.2 (2014): 507-512.
Chicago
Yu, F., Hong, Y., Qu, J., Chen, F., Li, T."The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome". International Journal of Molecular Medicine 34, no. 2 (2014): 507-512. https://doi.org/10.3892/ijmm.2014.1783