Human Molecular Genetics Advance Access originally published online on January 3, 2008
Human Molecular Genetics 2008 17(7):1043-1051; doi:10.1093/hmg/ddm377
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The PSORS1 locus gene CCHCR1 affects keratinocyte proliferation in transgenic mice
1 Department of Medical Genetics 2 Department of Dermatology 3 Department of Surgery, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland 4 Department of Anatomy, University of Kuopio, Finland 5 Department of Medical Sciences, Dermatology and Venereology, Uppsala University Hospital, Sweden 6 Division of Clinical Research Center 7 Division of Pathology 8 Division of Biosciences and Nutrition, Department of Laboratory Medicine, Huddinge University Hospital, Stockholm, Sweden 9 Department of Dermatology, Karolinska Institutet at Stockholm Söder Hospital, Stockholm, Sweden
* To whom correspondence should be addressed at: Department of Biosciences and Nutrition, Karolinska Institutet, 14157 Huddinge, Sweden. Tel: +46 734213550; Fax: +46 87745538; Email: juha.kere{at}biosci.ki.se
Received September 11, 2007; Accepted December 21, 2007
The CCHCR1 gene (Coiled-Coil 
-Helical Rod protein 1) within the major psoriasis susceptibility locus PSORS1 is a plausible candidate gene for the risk effect. We have previously generated transgenic mice overexpressing either the psoriasis-associated risk allele CCHCR1*WWCC or the normal allele of CCHCR1. All transgenic CCHCR1 mice appeared phenotypically normal, but exhibited altered expression of genes relevant to the pathogenesis of psoriasis, including upregulation of hyperproliferation markers keratins 6, 16 and 17. Here, we challenged the skin of CCHCR1 transgenic mice with wounding or 12-O-tetradecanoyl-13-acetate (TPA), treatments able to induce epidermal hyperplasia and proliferation that both are hallmarks of psoriasis. These experiments revealed that CCHCR1 regulates keratinocyte proliferation. Early wound healing on days 1 and 4 was delayed, and TPA-induced epidermal hyperproliferation was less pronounced in mice with the CCHCR1*WWCC risk allele than in mice with the normal allele or in wild-type animals. Finally, we demonstrated that overexpression of CCHCR1 affects basal keratinocyte proliferation in mice; CCHCR1*WWCC mice had less proliferating keratinocytes than the non-risk allele mice. Similarly, keratinocytes isolated from risk allele mice proliferated more slowly in culture than wild-type cells when measured by BrdU labeling and ELISA. Our data show that CCHCR1 may function as a negative regulator of keratinocyte proliferation. Thus, aberrant function of CCHCR1 may lead to abnormal keratinocyte proliferation which is a key feature of psoriatic epidermis.