title: Centrosomal localization of the psoriasis candidate gene product, CCHCR1, supports a role in cytoskeletal organization.
abstract: CCHCR1 (Coiled-Coil α-Helical Rod protein 1), within the major psoriasis susceptibility locus PSORS1, is a plausible candidate gene with the psoriasis associated risk allele CCHCR1*WWCC. Although its expression pattern in psoriatic skin differs from healthy skin and its overexpression influences cell proliferation in transgenic mice, its role as a psoriasis effector gene has remained unsettled. The 5'-region of the gene contains a SNP (rs3130453) that controls a 5'-extended open reading frame and thus the translation of alternative isoforms. We have now compared the function of two CCHCR1 isoforms: the novel longer isoform 1 and the previously studied isoform 3. In samples of Finnish and Swedish families, the allele generating only isoform 3 shows association with psoriasis (P<10(-7)). Both isoforms localize at the centrosome, a cell organelle playing a role in cell division. In stably transfected cells the isoform 3 affects cell proliferation and with the CCHCR1*WWCC allele, also apoptosis. Furthermore, cells overexpressing CCHCR1 show isoform- and haplotype-specific influences in the cell size and shape and alterations in the organization and expression of the cytoskeletal proteins actin, vimentin, and cytokeratins. The isoform 1 with the non-risk allele induces the expression of keratin 17, a hallmark for psoriasis; the silencing of CCHCR1 reduces its expression in HEK293 cells. CCHCR1 also regulates EGF-induced STAT3 activation in an isoform-specific manner: the tyrosine phosphorylation of STAT3 is disturbed in isoform 3-transfected cells. The centrosomal localization of CCHCR1 provides a connection to the abnormal cell proliferation and offers a link to possible cellular pathways altered in psoriasis.
authors.affiliation: Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Mari H
authors.initials: MH
authors.lastname: Tervaniemi
authors.forename: H Annika
authors.initials: HA
authors.lastname: Siitonen
authors.forename: Cilla
authors.initials: C
authors.lastname: Söderhäll
authors.forename: Gurinder
authors.initials: G
authors.lastname: Minhas
authors.forename: Jyrki
authors.initials: J
authors.lastname: Vuola
authors.forename: Inkeri
authors.initials: I
authors.lastname: Tiala
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.forename: Lena
authors.initials: L
authors.lastname: Samuelsson
authors.forename: Sari
authors.initials: S
authors.lastname: Suomela
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Outi
authors.initials: O
authors.lastname: Elomaa
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism*; D003001:Cloning, Molecular; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression; D023061:Gene Order; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D021381:Protein Transport; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C412616:CCHCR1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D050796:STAT3 Transcription Factor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors