Disease relevance of Ptch1

• Germ line inactivation of one copy of Ptch1 predisposes to basal cell carcinoma and medulloblastoma in mouse and man [1].
• Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice [2].
• Mice in which one copy of Ptch1 is inactivated show increased susceptibility to spontaneous tumor development and hypersensitivity to radiation-induced tumorigenesis, providing an ideal in vivo model to study the typical pathologies associated with basal cell nevus syndrome [2].
• The PATCHED (PTC) gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein that is defective in basal cell nevus syndrome (BCNS) [3].
• Mutations in mouse and human patched1 (ptc1) genes are associated with birth defects and cancer [4].

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

• We report here that treatment of cesium-137-irradiated Ptch1+/- mice with immunosuppressive doses of cyclosporine A plus prednisolone for 4-1/2 mo increased basal cell carcinoma burden by 2.5-fold [8].
• Topical tazarotene chemoprevention reduces Basal cell carcinoma number and size in Ptch1+/- mice exposed to ultraviolet or ionizing radiation [9].
• Here we report that Igf2 is indispensable for the formation of medulloblastoma and RMS in Ptch mutants [10].
• Both tumors are associated with a deficiency in the tumor suppressor Patched (PTCH) in Gorlin syndrome (Gorlin, R. J. (1987) Medicine (Baltimore) 66, 98-113), and they are present in the corresponding murine models [10].
• The authors aimed to study the temporal and spatial pattern of expression of Shh and its receptor Ptc1 during the development of the anterior foregut and to test the hypothesis that the Shh expression pattern is disturbed during the development of oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) in Adriamycin-treated mouse embryos [11].

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

• Hip encodes a membrane glycoprotein that binds to all three mammalian Hedgehog proteins with an affinity comparable to that of Ptc-1 [16].
• In contrast, mutations in Ptc1 reduce pancreas gene expression and impair glucose homeostasis [17].
• Furthermore, oral administration of the suicidal ODC inhibitor alpha-difluoromethylornithine reduced UVB-induced BCCs in Ptch1+/- mice [18].
• To further investigate this hypothesis, we submitted Ptc(+/-) heterozygous mutant mice and their wild-type littermates to chemical carcinogenesis by adding N-butyl-N-(4-hydroxybutyl) nitrosamine to their drinking water [19].
• The H4 leucine zipper-mediated dimerization is essential for tyrosine hyperphosphorylation and the transforming activity of the PTC1 oncoprotein [20].

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

• The present study has investigated additional molecular changes in RMSs of Ptch1 mutant mice by means of microarray analysis and protein expression analysis [28].
• In order to determine candidate genes involved in tumorigenesis of MB, we have screened tumors of heterozygous Ptch1 mice for differentially expressed genes by means of cDNA microarray technology [29].
• Immunization with either of two large recombinant Hip1 polypeptides was well tolerated in Ptch1+/- mice, induced B and T cell responses detectable by enzyme-linked immunosorbent assay, Western blot, delayed type hypersensitivity, and enzyme-linked immunospot assay, and reduced the number of BCCs by 42% (P < 0.001) and 32% (P < 0.01), respectively [30].
• Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice [18].
• Shh, Ptc, and Ptch2 were induced about six- to tenfold in normal embryonic hair germs in vivo as well as in developing skin tissue maintained in organ culture [31].

References