Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias

Kim, Mi‐Yeon; Park, Hyun Jeong; Baek, Seung-Cheol; Byun, Dae Gyoo; Houh, Dong

doi:10.1016/s0923-1811(01)00170-0

Cited by 99 publications

(93 citation statements)

References 18 publications

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“…4h), suggesting that activation of Hh signaling only is not sufficient for the inhibition of p53-mediated tumor suppression. This issue is also supported because mutations in both Ptch (or Smo) and p53 are often observed together in BCC tumors (36,37). We also showed that, in human breast cancer cell lines, the levels of p53 are decreased by activated Hh signaling and that inhibition of Hh signaling by KAAD cyclopamine results in accumulation of p53 (Fig.…”

Section: Discussionmentioning

confidence: 91%

Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2

Abe

Oda-Sato

Tobiume

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

130

123

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The hedgehog (Hh) signaling pathway regulates the development of many organs in mammals, and activation of this pathway is widely observed in human cancers. Although it is known that Hh signaling activates the expression of genes involved in cell growth, the precise role of the Hh pathway in cancer development is still unclear. Here, we show that constitutively activated mutants of oncogenesis ͉ ubiquitination ͉ cell growth ͉ apoptosis

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Section: Discussionmentioning

confidence: 91%

Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2

Abe

Oda-Sato

Tobiume

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

130

123

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“…8 In most cases, the abnormality represents a mutation in the human homologue of the Drosophila patched gene (PTCH). 25 Perturbation of this tumor suppressor gene on chromosome 9 q22-q31 26,27 results in upregulated cell proliferation. The biology of sporadic BCC and of tumors arising in the setting of nevoid BCC syndrome is discussed in greater detail below.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…25 A tumor suppressor gene, PTCH is sited on chromosome 9 q22-q31. 26 The PTCH gene product functions as a transmembrane receptor for the Sonic hedgehog (shh) protein; when binding of the wild-type protein occurs, the inhibition by PTCH of a second seven-span transmembrane protein termed Smoothened (smo) is downregulated. The inhibition of smo is held to be relieved by mutations of PTCH or SMO that eventuate in cell proliferation ( Figure 17); 65 PTCH gene mutations produce truncated proteins incapable of binding to and inactivating smo.…”

Section: Nevoid Bccmentioning

confidence: 99%

Basal cell carcinoma: biology, morphology and clinical implications

2006

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Basal cell carcinoma (BCC) is the most common malignant neoplasm of humans. Rising dramatically in incidence in North America, as likely reflects changing habits of the population and a move from more northerly climes to the sunbelt of the Southern and Southwestern United States, the incidence is surely to rise even higher in the future. The last decade has seen significant advances in our understanding of BCC biology and novel approaches to therapy, which hinge upon accurate diagnosis and subclassification by pathologists. The purpose of this review article is to summate the research advances in our understanding of BCC biology and to acquaint pathologists and clinicians to the practical issues in BCC diagnosis and subclassification which flow there from.

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“…It is possible that the reduced expression is related to p53 mutations; however, the p53 status in those BCC samples in the microarray, obtained from US Biomax, was not characterized. But it is noteworthy that p53 is mutated at a high frequency in BCC (22,23).…”

Section: Deletion Of P21 Accelerates Uv-induced Skin Cancers In Ddb2mentioning

confidence: 99%

p21 Cooperates with DDB2 Protein in Suppression of Ultraviolet Ray-induced Skin Malignancies

Stoyanova

Roy

Bhattacharjee

et al. 2012

Journal of Biological Chemistry

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Background:The p53-induced genes DDB2 and p21 play antagonistic roles in DNA repair and apoptosis. Results: In UV-induced skin carcinoma, DDB2 and p21 cooperate to prevent carcinoma by inducing premature senescence. Conclusion: Pro-senescence and anti-proliferative pathways are critical protection mechanism against skin malignancies. Significance: Although studies on skin cancer focus on DNA repair mechanisms, this study provides new insights.Exposure to ultraviolet rays (UV) in sunlight is the main cause of skin cancer. Here, we show that the p53-induced genes DDB2 and p21 are down-regulated in skin cancer, and in the mouse model they functionally cooperate to prevent UV-induced skin cancer. Our previous studies demonstrated an antagonistic role of DDB2 and p21 in nucleotide excision repair and apoptosis. Surprisingly, we find that the loss of p21 restores nucleotide excision repair and apoptosis in Ddb2 ؊/؊ mice, but it does not protect from UV-mediated skin carcinogenesis. In contrast, Ddb2 ؊/؊ p21 ؊/؊ mice are significantly more susceptible to UVinduced skin cancer than the Ddb2 ؊/؊ or the p21 ؊/؊ mice. We provide evidence that p21 deletion in the Ddb2 ؊/؊ background causes a strong increase in cell proliferation. The increased proliferation in the Ddb2 ؊/؊ p21 ؊/؊ background is related to a severe deficiency in UV-induced premature senescence. Also, the oncogenic pro-proliferation transcription factor FOXM1 is overexpressed in the p21 ؊/؊ background. Our results show that the anti-proliferative and the pro-senescence pathways of DDB2 and p21 are critical protection mechanisms against skin malignancies.The UV rays in sunlight cause DNA damage by generating cyclobutane pyrimidine dimers and 6-(1,2)-dihydro-2-oxo-4-pyrimidinyl-5-methyl-2,4-(1H,3H)-pyrimidinedione between two adjacent pyrimidines. Both DNA damages lead to distortion of DNA, predisposing cells to accumulate mutations. As a protective mechanism against UV-induced DNA damage, cells utilize nucleotide excision repair (NER) 6 pathway or they undergo apoptosis. Damaged DNA-binding protein 2 (DDB2), a subunit of the damaged DNA-binding protein DDB, encoded by the XP-E gene, plays important roles in both NER and apoptosis following exposure to UV irradiation (1-3). Ddb2 Ϫ/Ϫ mice develop UV-induced skin cancers with much higher incidence in comparison with wild type (WT) mice (4, 5). Enhanced expression of Ddb2 in mice also reduces UV-induced carcinogenesis by delaying the onset of tumor development and also by reducing the number of tumors per mouse, providing further evidence of the role of DDB2 in the inhibition of UV-induced skin tumorigenesis (6).We demonstrated that high accumulation of p21 following exposure to low doses of UV light is the cause for the NER deficiency in the fibroblasts derived from the Ddb2-deficient embryos. DDB2 regulates the level of p21 through multiple mechanisms. DDB2 targets p53 S18P for proteolysis upon low dose of UV irradiation, ensuring lower expression of its downstream transcriptional target p21 (7). DDB2 also targe...

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Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias

Cited by 99 publications

References 18 publications

Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2

Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2

Basal cell carcinoma: biology, morphology and clinical implications

p21 Cooperates with DDB2 Protein in Suppression of Ultraviolet Ray-induced Skin Malignancies

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