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Gene Review

Ptch1  -  patched homolog 1

Mus musculus

Synonyms: A230106A15Rik, PTC, PTC1, Patched 1, Protein patched homolog 1, ...
 
 
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Disease relevance of Ptch1

 

High impact information on Ptch1

  • It also appears to be necessary for appropriate modulation of signaling by the Shh receptor, Ptc1 [5].
  • Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1 [5].
  • A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region [6].
  • Despite extensive genetic studies demonstrating the importance of these receptor components in embryonic patterning and cancer, the mechanism by which Ptc regulates Smo is not understood [7].
  • Mutations affecting the transmembrane proteins Patched (Ptc) or Smoothened (Smo) that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with human tumours such as basal cell carcinoma (BCC) and medulloblastoma [7].
 

Chemical compound and disease context of Ptch1

 

Biological context of Ptch1

  • In many cases, medulloblastoma arising from perturbations of Ptch1 function leads to a concomitant up-regulation of a highly similar gene, Patched2 (Ptch2) [1].
  • This phenotype resembled that caused by loss of patched (Ptch1), another negative regulator of the Hh pathway [12].
  • In contrast to Ptch1 heterozygous mice, Sufu heterozygotes had no developmental defects and no apparent tumor predisposition [12].
  • The sonic hedgehog (SHH) receptor Patched 1 (Ptch1) is critical for embryonic development, and its loss is linked to tumorigenesis [1].
  • The resemblance of Sufu homozygotes to Ptch1 homozygotes is consistent with mouse Sufu being a conserved negative modulator of Hh signaling [12].
 

Anatomical context of Ptch1

  • We demonstrate that hedgehog (Hh) signaling in the neonatal intestine is paracrine, from epithelium to Ptch1-expressing subepithelial myofibroblasts (ISEMFs) and smooth muscle cells (SMCs) [13].
  • We have established mammalian cell lines with reduced Ptc1 function and a lacZ reporter to investigate Hh signal transduction [4].
  • Embryonic fibroblasts were derived from mice, heterozygous or homozygous for a ptc1 mutation that inserts lacZ under the control of the ptc1 promoter (ptc1-lacZ) [4].
  • Our results demonstrate that neither Shh nor Ihh is required for mammary gland morphogenesis and functional differentiation, suggesting that the two members of the Hedgehog family may have redundant function in activating the Ptc1 signaling pathway during mammary gland development [14].
  • RESULTS: Uninjured rat corneal epithelium was not labeled by anti-Shh antibody, but weakly positive for Ptc 1 [15].
 

Associations of Ptch1 with chemical compounds

 

Physical interactions of Ptch1

  • Different domains of Smo are involved in Ptc binding and activation of a Gli reporter construct [21].
  • CONCLUSIONS: These data demonstrate that Smo is the signaling component of a multicomponent Hh receptor complex and that Ptc is a ligand-regulated inhibitor of Smo [21].
 

Regulatory relationships of Ptch1

  • Thus Ptc appears to be essential for repression of genes that are locally activated by Shh [3].
  • Ptc represses expression of Hh target genes such as Gli1 and ptc1 itself [22].
  • In both areas, mRNA up-regulation of the transcriptional target gene Patched was observed in cells expressing the oligodendroglial transcription factor Olig1 [23].
  • RMS in Ptch mutant mice consistently contain elevated levels of the tumor growth-promoting insulin-like growth factor 2 (Igf2) [10].
 

Other interactions of Ptch1

  • Moreover, loss of Ptc or overexpression of Shh cannot be the sole causes of Gli1 induction and sporadic BCC formation, as they do not occur consistently [24].
  • Thus, Hip, like Ptc-1, is a general transcriptional target of Hedgehog signalling [16].
  • In addition, specific components in the Hedgehog pathway are either ectopically activated (Ptc, Ptc-2, Gli1) or repressed (Gli2) [25].
  • In contrast, medulloblastomas arising in Ptc1(+/-) mice lacking one or both Ink4c alleles retained p53 function and exhibited only limited genomic instability [26].
  • Msx1 is required for the induction of Patched by Sonic hedgehog in the mammalian tooth germ [27].
 

Analytical, diagnostic and therapeutic context of Ptch1

References

  1. Patched2 modulates tumorigenesis in patched1 heterozygous mice. Lee, Y., Miller, H.L., Russell, H.R., Boyd, K., Curran, T., McKinnon, P.J. Cancer Res. (2006) [Pubmed]
  2. Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice. Mancuso, M., Pazzaglia, S., Tanori, M., Hahn, H., Merola, P., Rebessi, S., Atkinson, M.J., Di Majo, V., Covelli, V., Saran, A. Cancer Res. (2004) [Pubmed]
  3. Altered neural cell fates and medulloblastoma in mouse patched mutants. Goodrich, L.V., Milenković, L., Higgins, K.M., Scott, M.P. Science (1997) [Pubmed]
  4. Several PATCHED1 missense mutations display activity in patched1-deficient fibroblasts. Bailey, E.C., Milenkovic, L., Scott, M.P., Collawn, J.F., Johnson, R.L. J. Biol. Chem. (2002) [Pubmed]
  5. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Lewis, P.M., Dunn, M.P., McMahon, J.A., Logan, M., Martin, J.F., St-Jacques, B., McMahon, A.P. Cell (2001) [Pubmed]
  6. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Hahn, H., Wicking, C., Zaphiropoulous, P.G., Gailani, M.R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A.B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D.J., Gerrard, B., Goldstein, A.M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A.E. Cell (1996) [Pubmed]
  7. Patched acts catalytically to suppress the activity of Smoothened. Taipale, J., Cooper, M.K., Maiti, T., Beachy, P.A. Nature (2002) [Pubmed]
  8. Anti-rejection drug treatment increases basal cell carcinoma burden in Ptch1+/- mice. Vogt, A., Hebert, J., Hwang, J., Lu, Y., Epstein, E.H. J. Invest. Dermatol. (2005) [Pubmed]
  9. Topical tazarotene chemoprevention reduces Basal cell carcinoma number and size in Ptch1+/- mice exposed to ultraviolet or ionizing radiation. So, P.L., Lee, K., Hebert, J., Walker, P., Lu, Y., Hwang, J., Kopelovich, L., Athar, M., Bickers, D., Aszterbaum, M., Epstein, E.H. Cancer Res. (2004) [Pubmed]
  10. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. Hahn, H., Wojnowski, L., Specht, K., Kappler, R., Calzada-Wack, J., Potter, D., Zimmer, A., Müller, U., Samson, E., Quintanilla-Martinez, L., Zimmer, A. J. Biol. Chem. (2000) [Pubmed]
  11. Role of Sonic hedgehog in the development of the trachea and oesophagus. Ioannides, A.S., Henderson, D.J., Spitz, L., Copp, A.J. J. Pediatr. Surg. (2003) [Pubmed]
  12. Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Cooper, A.F., Yu, K.P., Brueckner, M., Brailey, L.L., Johnson, L., McGrath, J.M., Bale, A.E. Development (2005) [Pubmed]
  13. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Madison, B.B., Braunstein, K., Kuizon, E., Portman, K., Qiao, X.T., Gumucio, D.L. Development (2005) [Pubmed]
  14. Differential requirements for shh in mammary tissue and hair follicle morphogenesis. Gallego, M.I., Beachy, P.A., Hennighausen, L., Robinson, G.W. Dev. Biol. (2002) [Pubmed]
  15. Sonic hedgehog expression and role in healing corneal epithelium. Saika, S., Muragaki, Y., Okada, Y., Miyamoto, T., Ohnishi, Y., Ooshima, A., Kao, W.W. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  16. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Chuang, P.T., McMahon, A.P. Nature (1999) [Pubmed]
  17. Regulation of pancreas development by hedgehog signaling. Hebrok, M., Kim, S.K., St Jacques, B., McMahon, A.P., Melton, D.A. Development (2000) [Pubmed]
  18. Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice. Tang, X., Kim, A.L., Feith, D.J., Pegg, A.E., Russo, J., Zhang, H., Aszterbaum, M., Kopelovich, L., Epstein, E.H., Bickers, D.R., Athar, M. J. Clin. Invest. (2004) [Pubmed]
  19. Accelerated induction of bladder cancer in patched heterozygous mutant mice. Hamed, S., LaRue, H., Hovington, H., Girard, J., Jeannotte, L., Latulippe, E., Fradet, Y. Cancer Res. (2004) [Pubmed]
  20. Leucine zipper-mediated dimerization is essential for the PTC1 oncogenic activity. Tong, Q., Xing, S., Jhiang, S.M. J. Biol. Chem. (1997) [Pubmed]
  21. Sonic hedgehog signaling by the patched-smoothened receptor complex. Murone, M., Rosenthal, A., de Sauvage, F.J. Curr. Biol. (1999) [Pubmed]
  22. Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal patterning in the neural tube. Goodrich, L.V., Jung, D., Higgins, K.M., Scott, M.P. Dev. Biol. (1999) [Pubmed]
  23. Increase of proliferating oligodendroglial progenitors in the adult mouse brain upon Sonic hedgehog delivery in the lateral ventricle. Loulier, K., Ruat, M., Traiffort, E. J. Neurochem. (2006) [Pubmed]
  24. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Dahmane, N., Lee, J., Robins, P., Heller, P., Ruiz i Altaba, A. Nature (1997) [Pubmed]
  25. Evidence that preaxial polydactyly in the Doublefoot mutant is due to ectopic Indian Hedgehog signaling. Yang, Y., Guillot, P., Boyd, Y., Lyon, M.F., McMahon, A.P. Development (1998) [Pubmed]
  26. Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors. Zindy, F., Uziel, T., Ayrault, O., Calabrese, C., Valentine, M., Rehg, J.E., Gilbertson, R.J., Sherr, C.J., Roussel, M.F. Cancer Res. (2007) [Pubmed]
  27. Msx1 is required for the induction of Patched by Sonic hedgehog in the mammalian tooth germ. Zhang, Y., Zhao, X., Hu, Y., St Amand, T., Zhang, M., Ramamurthy, R., Qiu, M., Chen, Y. Dev. Dyn. (1999) [Pubmed]
  28. Molecular characterization of Patched-associated rhabdomyosarcoma. Kappler, R., Calzada-Wack, J., Schnitzbauer, U., Koleva, M., Herwig, A., Piontek, G., Graedler, F., Adamski, J., Heinzmann, U., Schlegel, J., Hemmerlein, B., Quintanilla-Martinez, L., Hahn, H. J. Pathol. (2003) [Pubmed]
  29. Transcriptional up-regulation of Gadd45a in Patched-associated medulloblastoma. Kappler, R., Hess, I., Schlegel, J., Hahn, H. Int. J. Oncol. (2004) [Pubmed]
  30. Immunoprevention of basal cell carcinomas with recombinant hedgehog-interacting protein. Vogt, A., Chuang, P.T., Hebert, J., Hwang, J., Lu, Y., Kopelovich, L., Athar, M., Bickers, D.R., Epstein, E.H. J. Exp. Med. (2004) [Pubmed]
  31. Suppression of hair follicle development inhibits induction of sonic hedgehog, patched, and patched-2 in hair germs in mice. Yamago, G., Takata, Y., Furuta, I., Urase, K., Momoi, T., Huh, N. Arch. Dermatol. Res. (2001) [Pubmed]
 
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