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Seija-Liisa Karvonen

Publications and source records attributed to Seija-Liisa Karvonen.

8 recordsLinked to original sources
PubMed2007

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

The HCR gene, officially called Coiled-Coil alpha-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.

Animals↗
PubMed2006

[Not Available].

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Journal Article↗
PubMed2005

NF1 tumor suppressor in epidermal wound healing with special focus on wound healing in patients with type 1 neurofibromatosis.

Type 1 neurofibromatosis syndrome (NF1) has been linked with mutations of the NF1 gene which encodes tumor suppressor neurofibromin, a regulator of Ras-MAPK signaling. In human epidermis, keratinocytes express NF1 tumor suppressor and it may have a distinctive function in these cells during wound healing, such as regulating Ras activity. NF1 expression was first studied during the epidermal wound healing using suction blister method. NF1 gene expression increased both in hypertrophic and migrating zones of the healing epidermis, and also in dermal fibroblasts underneath the injury. This prompted us to study epidermal wound healing in NF1 patients. Wound healing efficiency was evaluated 4 days after blister induction by clinical, physiological and histological methods. Epidermal wound healing was equally effective in NF1 patients and healthy controls. In addition, dermal wound healing appears to function normally in NF1 patients based on retrospective and follow-up study of biopsy scars. Furthermore, the healing wounds were analyzed immunohistochemically for cell proliferation rate and Ras-MAPK activity. Neither epidermal keratinocytes nor dermal fibroblasts showed difference in the cell proliferation rate or Ras-MAPK activity between NF1 patients and controls. Interestingly, NF1 patients displayed increased cell proliferation rate and Ras-MAPK activity in periarteriolar tissue underneath the wound. The results of the study suggest that epidermal wound healing is not markedly altered in NF1 patients. Furthermore, NF1 protein seems not to have an important function as a Ras-MAPK regulator in epidermal keratinocytes or dermal fibroblasts but instead appears to be regulator of Ras-MAPK signaling in vascular tissues.

Cell Proliferation↗
PubMed2003

Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1.

The major susceptibility locus for psoriasis, PSORS1, resides on chromosome 6p and includes the candidate genes HLA-C, HCR, and CDSN. Based on a nationwide collection of psoriasis patients and genotyping for the PSORS1 susceptibility haplotype, we selected for a genome scan nine families who do not show association with PSORS1 to more easily detect minor loci for psoriasis susceptibility. In the genome scan, five loci gave initial evidence of linkage and were studied with a denser marker map. After fine mapping, only one locus on 18p11.23 showed suggestive evidence of linkage (nonparametric multipoint linkage analysis score, 3.58; p = 0.0038). The bootstrapping analysis showed that one large family contributed the majority of the linkage (p = 0.0039), but was supported by other families. Haplotype sharing between the linked families and haplotype association analysis gave additional support for the locus. Further, the 18p locus has shown nominal evidence of linkage with psoriasis in the British population. Taken together, these findings confirm the presence of a minor susceptibility locus for psoriasis on 18p11.

Adolescent↗
PubMed2003

Matrix metalloproteinase-19 is expressed by keratinocytes in psoriasis.

Keratinocyte hyperproliferation, inflammatory infiltrates, neoangiogenesis and alterations in cytokine levels are hallmarks of psoriatic skin. Matrix metalloproteinases (MMPs) have been associated with the remodeling of the extracellular matrix during inflammation, neovascularization, and malignant transformation. We have previously shown that particularly MMP-12 is abundantly expressed by macrophages and MMP-9 in macrophages and neutrophils of psoriatic lesions. In this work the expression of two novel metalloproteinases, MMP-19 and MMP-28, was investigated in psoriatic lesional and non-lesional skin. MMP-19 protein was detected by immunohistochemistry in 28/29 samples in keratinocytes in the same regions as Ki67 (marker of proliferating keratinocytes) and p63 (marker of keratinocyte stem cells). Immunosignaling was also seen in endothelial cells and fibroblasts. Furthermore, MMP-19 mRNA was upregulated in psoriatic keratinocytes and skin as assessed by quantitative real-time polymerase chain reaction. In lichen planus and lichenoid chronic dermatitis, MMP-19 staining was found in keratinocytes in areas where the basement membrane was abnormal. MMP-28 was not detected in psoriatic or non-lesional skin. Our results suggest that keratinocytes as well as the previously reported cell types (smooth muscle, endothelial and macrophages) can express MMP-19 in psoriasis and lichen planus. Upregulation of MMP-19 in keratinocytes may be influenced by changes in the architecture of the basement membrane zone.

Basement Membrane↗
PubMed2002

Altered calcium-mediated cell signaling in keratinocytes cultured from patients with neurofibromatosis type 1.

Capacitative calcium entry and calcium wave propagation were studied in keratinocytes cultured from control persons and patients with type 1 neurofibromatosis. The cells were stimulated mechanically in the presence of inhibitors of gap-junctional or ATP-mediated communication to determine which pathways are operative in Ca(2+) signaling between these cells. Keratinocytes cultured from patients with type 1 neurofibromatosis (NF1) had a tendency to form cultures with markedly altered calcium-related signaling characteristics. Specifically, the resting Ca(2+) levels, intracellular Ca(2+) stores, capacitative calcium influx, and gap-junctional signal transduction were defective in NF1 keratinocytes. Western transfer analysis revealed apparently equal connexin 43 protein levels in normal control and in NF1 keratinocytes. Indirect immunofluorescence, however, demonstrated that connexin 43 was relatively evenly distributed in NF1 cells and did not form typical gap-junctional plaques between keratinocytes. Furthermore, the speed of the calcium wave was reduced in NF1 cells compared to normal keratinocytes. The results demonstrate that keratinocytes cultured from patients with NF1 display altered calcium-mediated signaling between cells.

Adenosine Triphosphate↗
PubMed2002

NF1 tumor suppressor mRNA is targeted to the cell-cell contact zone in Ca(2+)-induced keratinocyte differentiation.

SUMMARY: We have previously shown that NF1 (type 1 neurofibromatosis) p21ras GTPase-activating tumor suppressor protein undergoes major relocalization during the formation of cell-cell junctions in differentiating keratinocytes in vitro. This prompted us to study the distribution of NF1 mRNA under the same conditions by in situ hybridization. In differentiating keratinocytes, the NF1 mRNA signal intensified within the cell cytoplasm within the first 0.5 to 2 hours after induction of cellular differentiation. First, the hybridization signal was evenly distributed throughout the cytoplasm. Subsequently, NF1 mRNA was gradually polarized to the cellular periphery at the side of cell-cell junctions and finally disappeared. Reappearance of NF1 mRNA was found in migrating keratinocytes forming a bilayered culture. Disruption of microfibrillar cytoskeleton, but not microtubules, caused a marked change in the subcellular distribution of NF1 mRNA. This data may suggest that intact actin microfilaments are essential for transport of NF1 mRNA to the cell periphery. This is the first study demonstrating that NF1, or any tumor suppressor mRNA, belongs to a rare group of mRNAs not targeted to free polysomes or ribosomes of the rough endoplasmic reticulum. This finding recognizes a potential way for post-transcriptional modification of NF1 expression.

Adult↗