High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene

Nakane, Hironobu; Takeuchi, Seiji; Yuba, Shunsuke; Saijo, Masafumi; Nakatsu, Yoshimichi; Murai, Hiroaki; Nakatsuru, Yoko; Ishikawa, Takatoshi; Hirota, Seiichi; Kitamura, Yukihiko; Kato, Yuki; Tsunoda, Yukio; Miyauchi, Hiroko; Horio, Takeshi; Tokunaga, Tomoyuki; Matsunaga, Tsukasa; Nikaido, Osamu; Nishimune, Yoshitake; Okada, Yoshio; Tanaka, Kiyoji

doi:10.1038/377165a0

Cited by 275 publications

(194 citation statements)

References 15 publications

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“…XP is characterized by extreme sensitivity to UV light, resulting in advanced degenerative changes on sun-exposed areas of the skin and eyes and a high predisposition to cancer. Deletion of NER genes in experimental animals that are then subjected to UV carcinogenesis protocols has corroborated these findings, demonstrating that NER is a primary defense against UV-induced cancer (de Vries et al, 1995;Nakane et al, 1995;Sands et al, 1995;Berg et al, 2000).…”

Section: Introductionsupporting

confidence: 54%

Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

et al. 2005

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The E2F1 transcription factor regulates the expression of genes involved in cell proliferation, apoptosis and DNA repair. Following DNA damage, E2F1 is phosphorylated and stabilized, but the physiological role of E2F1 in the response to DNA damage is unclear. We find that mice lacking E2F1 have increased levels of epidermal apoptosis compared to wild-type mice following exposure to ultraviolet B (UVB) radiation. Moreover, transgenic overexpression of E2F1 in basal layer keratinocytes suppresses apoptosis induced by UVB. Inhibition of UVB-induced apoptosis by E2F1 is unexpected given that most studies have demonstrated a proapoptotic function for E2F1. E2F1-mediated suppression of apoptosis does not involve alterations in mitogen-activated protein kinase activation or Bcl-2 downregulation in response to UVB and is independent of p53. Instead, inhibition of UVBinduced apoptosis by E2F1 correlates with a stimulation of DNA repair. Mice lacking E2F1 are impaired for the removal of DNA photoproducts, while E2F1 transgenic mice repair UVB-induced DNA damage at an accelerated rate compared to wild-type mice. These findings suggest that E2F1 participates in the response to UVB by promoting DNA repair and suppressing apoptosis.

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Section: Introductionsupporting

confidence: 54%

Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

et al. 2005

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“…Mice harboring mutation in the XPA or XPC gene did not develop spontaneous tumors, however, they developed tumors at a high frequency upon UVB irradiation for a period of 20-30 weeks (Nakane et al, 1995;Sands et al, 1995). A recent study on DDB2À/À mice reported high incidences of UV-induced skin carcinogenesis (Itoh et al, 2004).…”

Section: Ddb2à/à Mice Are Susceptible To Uv-induced Skin Cancersmentioning

confidence: 99%

Tumor-prone phenotype of the DDB2-deficient mice

et al. 2004

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DDB2 is an essential subunit of the damaged-DNA recognition factor DDB, which is involved in global genomic repair in human cells. Moreover, DDB2 is mutated in the repair-deficiency disease xeroderma pigmentosum (Group E). Expression of DDB2 in human cells is induced by P53, BRCA1 and by ionizing radiation. The DDB2 protein associates with transcriptional activator and coactivator proteins. In addition, DDB2 in conjunction with DDB1 associates with cullin 4A and the Cop9/signalosome. We generated a mouse strain deficient for DDB2 (DDB2À/À). Consistent with the human disease (XP-E), the DDB2À/À mice were susceptible to UV-induced skin carcinogenesis. We observed a significant difference in the initial rate of cyclobutane pyrimidine dimer (CPD)-removal from the skin following UV irradiation. Also, the DDB2-deficient mice exhibited a significantly reduced life span compared to their wild-type littermates. Moreover, unlike other XP-deficient mice, the DDB2-deficient mice developed spontaneous malignant tumors at a high rate between the ages of 20 and 25 months. The observations suggest that, in addition to DNA repair, the other interactions of DDB2 are significant in its tumor suppression function.

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“…Therefore, overexpression of a stem cell factor, the ligand for the c-Kit receptor tyrosine kinase, may induce malignant melanomas in UV-irradiated mouse skin (71). As a comparison, NER-deficient mice, such as XPA-deficient mice (15,48) and XPC-deficient mice (8, 53), do not get melanomas.…”

Section: Polh-deficient Mice As An Xp-v Modelmentioning

confidence: 99%

UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

Ohkumo

Kondo

Yokoi

et al. 2006

Molecular and Cellular Biology

105

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DNA polymerase(Pol ) is the product of the Polh gene, which is responsible for the group variant of xeroderma pigmentosum, a rare inherited recessive disease which is characterized by susceptibility to sunlightinduced skin cancer. We recently reported in a study of Polh mutant mice that Pol is involved in the somatic hypermutation of immunoglobulin genes, but the cancer predisposition of Polh ؊/؊ mice has not been examined until very recently. Another translesion synthesis polymerase, Pol , a Pol paralog encoded by the Poli gene, is naturally deficient in the 129 mouse strain, and the function of Pol is enigmatic. Here, we generated Polh Poli doubledeficient mice and compared the tumor susceptibility of them with Polh-or Poli-deficient animals under the same genetic background. While Pol deficiency does not influence the UV sensitivity of mouse fibroblasts irrespective of Polh genotype, Polh Poli double-deficient mice show slightly earlier onset of skin tumor formation. Intriguingly, histological diagnosis after chronic treatment with UV light reveals that Pol deficiency leads to the formation of mesenchymal tumors, such as sarcomas, that are not observed in Polh ؊/؊ mice. These results suggest the involvement of the Pol and Pol proteins in UV-induced skin carcinogenesis.

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High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene

Cited by 275 publications

References 15 publications

Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

Tumor-prone phenotype of the DDB2-deficient mice

UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

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