Journal of Molecular Medicine

, Volume 85, Issue 6, pp 589–601

The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and downregulated in cultured psoriatic keratinocytes

  • Inkeri Tiala
  • Sari Suomela
  • Jari Huuhtanen
  • Janica Wakkinen
  • Maarit Hölttä-Vuori
  • Kati Kainu
  • Sirpa Ranta
  • Ursula Turpeinen
  • Esa Hämäläinen
  • Hong Jiao
  • Seija-Liisa Karvonen
  • Elina Ikonen
  • Juha Kere
  • Ulpu Saarialho-Kere
  • Outi Elomaa
Original Article

DOI: 10.1007/s00109-006-0155-0

Cite this article as:
Tiala, I., Suomela, S., Huuhtanen, J. et al. J Mol Med (2007) 85: 589. doi:10.1007/s00109-006-0155-0

Abstract

The HCR gene, officially called Coiled-Coil α-Helical Rod protein 1 (CCHCR1), located within the major psoriasis susceptibility locus PSORS1, is a plausible candidate gene for the risk effect. Recently, CCHCR1 was shown to promote steroidogenesis by interacting with the steroidogenic acute regulator protein (StAR). Here, we examined the role of CCHCR1 in psoriasis and cutaneous steroid metabolism. We found that CCHCR1 and StAR are expressed in basal keratinocytes in overlapping areas of the human skin, and CCHCR1 stimulated pregnenolone production in steroidogenesis assay. Overexpression of either the CCHCR1*WWCC risk allele or the non-risk allele enhanced steroid synthesis in vitro. Furthermore, the cytochrome P450scc enzyme was expressed in human keratinocytes and was induced by forskolin, a known activator of steroidogenesis, and forskolin also upregulated CCHCR1. CCHCR1 has an altered expression pattern in lesional psoriatic skin compared to normal healthy skin, suggesting its dysregulation in psoriasis. We found that the expression of CCHCR1 is downregulated twofold at the mRNA level in cultured non-lesional psoriatic keratinocytes when compared to non-psoriatic healthy cells. Our results also suggest a connection between CCHCR1 and vitamin D metabolism in keratinocytes. The expression of the vitamin D receptor (VDR) gene was lower in non-lesional psoriatic keratinocytes than in healthy cells. Furthermore, Vdr expression was downregulated in the keratinocytes of mice overexpressing the CCHCR1*WWCC risk allele when compared to keratinocytes from mice with the non-risk allele of CCHCR1. Finally, we demonstrate that other agents relevant for psoriasis and/or the regulation of steroidogenesis influence CCHCR1 expression in keratinocytes, including insulin, EGF, cholesterol, estrogen, and cyclosporin A. Taken the role of steroid hormones, including vitamin D and estrogen, in cell proliferation, epidermal barrier homeostasis, differentiation, and immune response, our results suggest a role for CCHCR1 in the pathogenesis of psoriasis via the regulation of skin steroid metabolism.

Keywords

Vitamin DSteroidogenic acute regulatory protein (StAR)P450 side chain cleavage enzyme (P450scc)PSORS1

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Inkeri Tiala
    • 1
  • Sari Suomela
    • 2
  • Jari Huuhtanen
    • 2
  • Janica Wakkinen
    • 1
  • Maarit Hölttä-Vuori
    • 3
  • Kati Kainu
    • 1
    • 2
  • Sirpa Ranta
    • 4
  • Ursula Turpeinen
    • 4
  • Esa Hämäläinen
    • 4
  • Hong Jiao
    • 5
  • Seija-Liisa Karvonen
    • 2
  • Elina Ikonen
    • 3
  • Juha Kere
    • 1
    • 5
    • 6
  • Ulpu Saarialho-Kere
    • 2
    • 7
  • Outi Elomaa
    • 1
  1. 1.Department of Medical GeneticsUniversity of HelsinkiHelsinkiFinland
  2. 2.Department of DermatologyUniversity of Helsinki and Helsinki University Central HospitalHelsinkiFinland
  3. 3.Institute of Biomedicine/AnatomyUniversity of HelsinkiHelsinkiFinland
  4. 4.Laboratory of Women’s Clinic and Department of Clinical ChemistryUniversity of Helsinki and Helsinki University Central HospitalHelsinkiFinland
  5. 5.Department of Biosciences and NutritionKarolinska InstitutetHuddingeSweden
  6. 6.Clinical Research CenterKarolinska University Hospital (Huddinge)StockholmSweden
  7. 7.Department of DermatologyKarolinska Institutet at Stockholm Söder HospitalStockholmSweden