Human Homolog of
            <b>
              <i>patched</i>
            </b>
            , a Candidate Gene for the Basal Cell Nevus Syndrome

Johnson, Ronald L.; Rothman, Alana; Xie, Jingwu; Goodrich, Lisa V.; Bare, John W.; Bonifas, Jeannette M.; Quinn, Anthony G.; Myers, R; Cox, David; Epstein, Ervin; Scott, Matthew P.

doi:10.1126/science.272.5268.1668

Cited by 1,754 publications

(1,135 citation statements)

References 58 publications

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“…Deregulation of HH signaling causes malformation and tumor formation, with the first example being basal cell carcinomas (BCC) (Johnson et al, 1996;Hahn et al, 1996b). In a number of tumors that were recently found to include prostatic and pancreatic cancers, HH signaling is abnormally upregulated, and effective signaling inhibition can repress tumor growth and induce apoptosis (Sanchez et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…PTCH1 is reported to have at least four first exons, 1, 1A, 1B and 1C (Johnson et al, 1996;Hahn et al, 1996a, b;Kogerman et al, 2002;Shimokawa et al, 2004;Nagao et al, 2005), and moreover undergoes exon skipping (Smyth et al, 1998;Nagao et al, 2005) or alternative exon insertion events (Uchikawa et al, 2006). The alternative promoters for exons 1B and 1C have GLI1 binding sites, consequently HH signaling activation results in upregulation of both PTCH1-1B and -1C (Shimokawa et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

et al. 2007

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Patched1 (PTCH1) is one of the key molecules involved in the Hedgehog (HH) signaling pathway and acts as the receptor of HH ligands. Additionally, PTCH1 inhibits the positive signal transductor Smoothened (SMO). Several PTCH1 splice variants are known but the functional differences among them are not clear. Here, we demonstrate the unique biological properties of the PTCH1 isoforms generated by alternative first exon usage. All isoforms examined worked as functional receptors of both Sonic HH and Desert HH. However, the signaling upregulated isoforms PTCH1-1B and -1C inhibited SMO and the pathway transcription factors glioma 1 (GLI1) and GLI2 to a higher extent than PTCH1-1 and -1Ckid. Moreover, in situ hybridizations allowed the detection of the Ptch1 isoforms in specific structures of the developing mouse embryo. Additionally, the differences in the N-terminal tail had a dramatic influence on the steady states of the proteins, with PTCH1-1B and -1C levels being significantly higher than PTCH1-1 and -1Ckid. This implies that the pronounced signaling inhibitory properties of PTCH1-1B and -1C may be mostly due to this high-protein expression rather than to intrinsic functional differences. Thus, our study supports a role of splicing variation and promoter choice for HH signaling regulation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

et al. 2007

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“…HH‐mediated hyperactivation of the zinc finger transcription factors GLI1 and GLI2 results in a malignant expression profile driving tumor growth (Fig. 1 a ) 2, 3, 4, 5, 6…”

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confidence: 99%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin‐6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis‐regulatory sequences by co‐binding of GLI and STAT3 to common HH‐IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI‐driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH‐IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

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“…Bases moléculaires du syndrome de Gorlin : mutations du gène PATCHED Les bases moléculaires du syndrome de Gorlin sont connues depuis 1996 avec l'identification de mutations germinales dans le gène PATCHED associées à la maladie [6,7]. PATCHED code pour le récepteur de la protéine diffusible morphogène Sonic Hedgehog (SHH), orthologue humain de Hedgehog (Hh) identifiée chez la drosophile, et qui est essentielle à la polarisation des segments au cours du développement embryonnaire.…”

Section: Le Syndrome De Gorlinunclassified

“…Dans le système nerveux central, seules deux voies de migration ont été défi-nies : les cellules progénitrices nées des CSN de la zone sous-ventriculaire migrent suivant le courant de migration rostrale, route unidirectionnelle menant aux bulbes olfactifs, et celles nées de la zone sous-granulaire migrent sur une courte distance dans la couche de cellules granulaires du gyrus dentelé [7]. Les mécanismes et les signaux qui orientent la migration des CSN adultes sont peu connus.…”

Section: Gliunclassified