Document Detail

Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures.
MedLine Citation:
PMID:  16510579     Owner:  NLM     Status:  MEDLINE    
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.
Arne van Schanke; Gemma M C A L van Venrooij; Marjan J Jongsma; H Alexander Banus; Leon H F Mullenders; Henk J van Kranen; Frank R de Gruijl
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  66     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-03-02     Completed Date:  2006-04-18     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2608-15     Citation Subset:  IM    
Dermatology Department, University Medical Centre Utrecht, Utrecht, the Netherlands.
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MeSH Terms
Carcinoma, Squamous Cell / etiology,  genetics
Cyclin-Dependent Kinase Inhibitor p16 / deficiency,  genetics*
Melanoma, Experimental / etiology,  genetics
Mice, Knockout
Neoplasms, Radiation-Induced / chemically induced,  etiology*,  genetics
Nevus / etiology*,  genetics
Sarcoma / etiology,  genetics
Skin Neoplasms / chemically induced,  etiology*,  genetics
Tumor Suppressor Protein p14ARF / deficiency,  genetics*
Ultraviolet Rays
Xeroderma Pigmentosum Group A Protein / genetics*
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p16; 0/Tumor Suppressor Protein p14ARF; 0/Xeroderma Pigmentosum Group A Protein; 0/Xpa protein, mouse; 57-97-6/9,10-Dimethyl-1,2-benzanthracene

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