The PSORS1 locus gene CCHCR1 affects keratinocyte proliferation in transgenic mice.
The CCHCR1 gene (Coiled-Coil alpha-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.
Tiala
Inkeri
I
Department of Medical Genetics, University of Helsinkiand Helsinki University Central Hospital, Helsinki, Finland.
Wakkinen
Janica
J
Suomela
Sari
S
Puolakkainen
Pauli
P
Tammi
Raija
R
Forsberg
Sofi
S
Rollman
Ola
O
Kainu
Kati
K
Rozell
Björn
B
Kere
Juha
J
Saarialho-Kere
Ulpu
U
Elomaa
Outi
O
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D006965:Hyperplasia / Q000139:chemically induced; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D011565:Psoriasis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D014945:Wound Healing
C412616:CCHCR1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D013755:Tetradecanoylphorbol Acetate