Activating Smoothened mutations in sporadic basal-cell carcinoma

@article{Xie1998ActivatingSM,
  title={Activating Smoothened mutations in sporadic basal-cell carcinoma},
  author={Jingwu Xie and Maximilien Murone and Shiuh-Ming Luoh and Anne M. Ryan and Qimin Gu and Chao-hui Zhang and Jeannette M. Bonifas and Ching-Wan Lam and Mary Hynes and Audrey San Francisco Goddard and Arnon Rosenthal and Ervin H. Epstein and Frederic j. de Sauvage},
  journal={Nature},
  year={1998},
  volume={391},
  pages={90-92}
}
Basal-cell carcinomas (BCCs) are the commonest human cancer. Insight into their genesis came from identification of mutations in the PATCHED gene (PTCH) in patients with the basal-cell nevus syndrome, a hereditary disease characterized by multiple BCCs and by developmental abnormalities. The binding of Sonic hedgehog (SHH) to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of Smoothened (SMO), a seven-span transmembrane protein,. According to this model, the inhibition of… Expand
Basal Cell Carcinoma and Its Development
TLDR
It is shown that unirradiated mice develop putative BCC precursor lesions, i.e., basaloid hyperproliferation areas arising from both follicular and interfollicular epithelium, and that these lesions progress to nodular and infiltrative BCCs only in irradiated mice. Expand
Functional Analysis of Novel Sonic Hedgehog Gene Mutations Identified in Basal Cell Carcinomas from Xeroderma Pigmentosum Patients
TLDR
It is reported for the first time, significant levels of SHH mutations found only in XP BCCs and none in squamous cell carcinomas, indicating their importance in the specific development of BCCs. Expand
Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.
TLDR
The results indicate that both PTCH and SMOH represent important targets for genetic alterations in sporadic BCCs and PNETs. Expand
A frequent activated smoothened mutation in sporadic basal cell carcinomas
TLDR
The finding of a high smoothened mutation rate, together with high frequent patched gene mutations reported recently, indicates that activation of the hedgehog signal transduction pathway is the most common and early event in the development of sporadic BCCs. Expand
Mutations in SUFU predispose to medulloblastoma
TLDR
It is reported that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Expand
Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma
TLDR
It was found that the expressions of ptc and smo mRNA were enhanced in the tumor nests of the nodular BCC, especially at the advancing portions, but were under the detectable level in the superficial BCC cases examined, indicating that pTC and sme mRNA expressions might be associated with BCC tumor progression and divide the BCC histologic types into two subtypes, superficial and nodular types. Expand
Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1.
TLDR
It is firmly established that increased GLI-1 expression is central and probably sufficient for tumor development and suggest that GLi-1-induced tumor development does not depend on additional p53 or Ha ras mutations. Expand
Understanding the Molecular Genetics of Basal Cell Carcinoma
TLDR
It is clear that a more complex genetic network of cancer-associated genes than previously hypothesized is involved in BCC carcinogenesis, with a potential impact on the development of new molecular targeted therapies. Expand
Sonic hedgehog signaling in basal cell carcinomas.
TLDR
The molecular mechanisms involved in alterations of the hedgehog signaling pathway that lead to the formation of basal cell carcinomas are being unraveled and has already allowed the investigation of future therapeutic strategies for treating these skin cancers. Expand
The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview
TLDR
Studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients are reviewed, and the emerged NBCCS fibroblast profile is matched to those of CAF to compare the impact of cell autonomous “pre-activated state” due to PTCH1 mutations toThose of skin tumor stroma. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 24 REFERENCES
The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas
TLDR
Northern blots and RNA in situ hybridization showed that patched is expressed at high levels in tumour cells but not normal skin suggesting that mutational inactivation of the gene leads to overexpression of mutant transcript owing to failure of a negative feedback mechanism. Expand
Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome
TLDR
It is proposed that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. Expand
Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation.
TLDR
It is demonstrated that a germ-line PTCH frameshift deletion in one patient with NBCCS was accompanied by loss of the normal copy of PTCH in a tumor developed in the same patient, illustrating two different mechanisms ofPTCH inactivation in different tumors derived from the same NBCCS patient. Expand
Basal cell carcinomas in mice overexpressing sonic hedgehog.
TLDR
It is shown here that transgenic mice overexpressing SHH in the skin develop many features of basal cell nevus syndrome, demonstrating that SHH is sufficient to induce basal cell carcinomas in mice, suggesting thatSHH may have a role in human tumorigenesis. Expand
Sporadic medulloblastomas contain PTCH mutations.
TLDR
Data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas, and it is interesting that all three mutations occur in exon 17 of the PTCH gene. Expand
Human Homolog of patched, a Candidate Gene for the Basal Cell Nevus Syndrome
  • Ronald L. Johnson, Alana L. Rothman, +8 authors Matthew P. Scott
  • Biology, Medicine
  • Science
  • 1996
TLDR
Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene, which appears to be crucial for proper embryonic development and for tumor suppression. Expand
Mutations in the human homologue of the Drosophila patched gene in Caucasian and African-American nevoid basal cell carcinoma syndrome patients.
TLDR
Several mutations in the human homologue (PTCH) of the Drosophila segment polarity gene patched have been identified in NBCCS patients as well as tumors associated with this syndrome. Expand
Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors.
TLDR
It is found that 2 of 14 sporadic medulloblastomas bear somatic nonsense mutations in one copy of the gene and also deletion of the other copy, and that missense mutations in PTCH are identified in two of seven breast carcinomas, one of nine meningiomas, and one colon cancer cell line. Expand
Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.
TLDR
The preponderance of truncation mutants in the germ line of NBCCS patients suggests that the developmental defects associated with the disorder are most likely due to haploinsufficiency, and the notion that PTCH may have a transport function is supported. Expand
The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog
TLDR
It is shown that Re can form a physical complex with a newly cloned vertebrate homologue of the Drosophila protein Smoothened (vSmo), and that vSmo is coexpressed with vPtc in many tissues but does not bind Shh directly. Expand
...
1
2
3
...