Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures.

2.50
Hdl Handle:
http://hdl.handle.net/10029/7145
Title:
Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures.
Authors:
Schanke, Arne van; Venrooij, Gemma M C A L van; Jongsma, Marjan J; Banus, H Alexander; Mullenders, Leon H F; Kranen, Henk J van; Gruijl, Frank R de
Abstract:
Nevi and melanomas correlate to childhood and intermittent solar UV exposure, xeroderma pigmentosum patients run increased risk, and p16(Ink4a) expression is often lost in malignant progression. To ascertain the effect of these risk factors, pigmented hairless Ink4a/Arf-, Xpa- knockout mice were subjected to various combinations of neonatal [7,12-dimethylbenz(a)anthracene (DMBA) or UVB exposure] and adult treatments (12-O-tetradecanoylphorbol-13-acetate or subacute daily UVB exposure or intermittent overexposure). Nevi occurred earliest, grew largest, and were most numerous in mice exposed to DMBA followed by intermittent UVB overexposure [effect of six minimal edemal doses (MED), 1 x /2 weeks > 4 MED 1 x /wk]. Neonatal UV exposure enhanced nevus induction but lost its effect after 200 days. The Xpa(-/-) mice proved exquisitely sensitive to UV-driven nevus induction, indicating the involvement of pyrimidine dimer DNA lesions, but Xpa(+/+) mice developed many more nevi (>40 per mouse) at high UV dosages not tolerated by Xpa(-/-) mice. Ink4a/Arf(-/-) mice developed most skin tumors faster, but surprisingly developed nevi slower than their heterozygous counterparts especially after neonatal UV exposure. Despite raising >1,600 nevi, only six melanomas arose in our experiments with Ink4a/Arf knockout mice (five of which in Xpa(+/+) mice at high UV dosages). In contrast to human nevi, these nevi lacked hotspot mutations in Braf or Ras genes, possibly explaining the lack of malignant progression in the Ink4a/Arf(-/-) mice. Hence, although our experiments did not effectively emulate human melanoma, they provided clear evidence that intermittent UV overexposure strongly stimulates and the Ink4a/Arf(-/-) genotype may actually impair nevus development.
Citation:
Cancer Res. 2006, 66(5):2608-15
Issue Date:
1-Mar-2006
URI:
http://hdl.handle.net/10029/7145
DOI:
10.1158/0008-5472.CAN-05-2476
PubMed ID:
16510579
Type:
Article
Language:
en
ISSN:
0008-5472
Appears in Collections:
Public Health and Health Care

Full metadata record

DC FieldValue Language
dc.contributor.authorSchanke, Arne van-
dc.contributor.authorVenrooij, Gemma M C A L van-
dc.contributor.authorJongsma, Marjan J-
dc.contributor.authorBanus, H Alexander-
dc.contributor.authorMullenders, Leon H F-
dc.contributor.authorKranen, Henk J van-
dc.contributor.authorGruijl, Frank R de-
dc.date.accessioned2007-01-10T10:08:29Z-
dc.date.available2007-01-10T10:08:29Z-
dc.date.issued2006-03-01-
dc.identifier.citationCancer Res. 2006, 66(5):2608-15en
dc.identifier.issn0008-5472-
dc.identifier.pmid16510579-
dc.identifier.doi10.1158/0008-5472.CAN-05-2476-
dc.identifier.urihttp://hdl.handle.net/10029/7145-
dc.description.abstractNevi and melanomas correlate to childhood and intermittent solar UV exposure, xeroderma pigmentosum patients run increased risk, and p16(Ink4a) expression is often lost in malignant progression. To ascertain the effect of these risk factors, pigmented hairless Ink4a/Arf-, Xpa- knockout mice were subjected to various combinations of neonatal [7,12-dimethylbenz(a)anthracene (DMBA) or UVB exposure] and adult treatments (12-O-tetradecanoylphorbol-13-acetate or subacute daily UVB exposure or intermittent overexposure). Nevi occurred earliest, grew largest, and were most numerous in mice exposed to DMBA followed by intermittent UVB overexposure [effect of six minimal edemal doses (MED), 1 x /2 weeks > 4 MED 1 x /wk]. Neonatal UV exposure enhanced nevus induction but lost its effect after 200 days. The Xpa(-/-) mice proved exquisitely sensitive to UV-driven nevus induction, indicating the involvement of pyrimidine dimer DNA lesions, but Xpa(+/+) mice developed many more nevi (>40 per mouse) at high UV dosages not tolerated by Xpa(-/-) mice. Ink4a/Arf(-/-) mice developed most skin tumors faster, but surprisingly developed nevi slower than their heterozygous counterparts especially after neonatal UV exposure. Despite raising >1,600 nevi, only six melanomas arose in our experiments with Ink4a/Arf knockout mice (five of which in Xpa(+/+) mice at high UV dosages). In contrast to human nevi, these nevi lacked hotspot mutations in Braf or Ras genes, possibly explaining the lack of malignant progression in the Ink4a/Arf(-/-) mice. Hence, although our experiments did not effectively emulate human melanoma, they provided clear evidence that intermittent UV overexposure strongly stimulates and the Ink4a/Arf(-/-) genotype may actually impair nevus development.en
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dc.format.mimetypeapplication/pdf-
dc.language.isoenen
dc.titleInduction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures.en
dc.typeArticleen
dc.format.digYES-

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