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- Title
Hailey-Hailey disease and tight junctions: Claudins 1 and 4 are regulated by ATP2C1 gene encoding Ca<sup>2+</sup>/Mn<sup>2+</sup> ATPase SPCA1 in cultured keratinocytes.
- Authors
Raiko, Laura; Siljamäki, Elina; Mahoney, Mỹ G.; Putaala, Heli; Suominen, Erkki; Peltonen, Juha; Peltonen, Sirkku
- Abstract
Mutations in the ATP2C1 gene encoding Ca2+/Mn2+ ATPase SPCA1 cause Hailey-Hailey disease ( HHD, OMIM 16960). HHD is characterized by epidermal acantholysis. We attempted to model HHD using normal keratinocytes, in which the SPCA1 mRNA was down-regulated with the small inhibitory RNA (si RNA) method. Si RNA inhibition significantly down-regulated the SPCA1 mRNA, as demonstrated by qPCR, and decreased the SPCA1 protein beyond detectable level, as shown by Western analysis. The expression of selected desmosomal, adherens and tight junction ( TJ) proteins was then studied in the SPCA1-deficient and control keratinocytes cultured in low (0.06 m m) or high (1.2 m m) calcium concentration. The mRNA and protein levels of most TJ components were up-regulated in non-treated control keratinocyte cultures upon switch from low to high calcium concentration. In contrast, SPCA1-deficient keratinocytes displayed high levels of TJ proteins claudins 1 and 4 even in low calcium. ZO-1 did not, however, follow similar expression patterns. Protein levels of occludin, beta-catenin, E-cadherin, desmoplakin, desmogleins 1-3, desmocollin 2/desmocollin 3 and plakoglobin did not show marked changes in SPCA1-deficient keratinocytes. Indirect immunofluorescence labelling revealed delayed translocation of desmoplakin and desmoglein 3 in desmosomes and increased intracellular pools of TJ and desmosomal components in SPCA1-inhibited keratinocytes. The results show that SPCA1 regulates the levels of claudins 1 and 4, but does not affect desmosomal protein levels, indicating that TJ proteins are differently regulated. The results also suggest a potential role for claudins in HHD.
- Subjects
CLAUDINS; ADENOSINE triphosphate; EPIDERMOLYSIS bullosa; MESSENGER RNA; IMMUNOFLUORESCENCE; DESMOGLEINS; DESMOPLAKIN; THERAPEUTICS
- Publication
Experimental Dermatology, 2012, Vol 21, Issue 8, p586
- ISSN
0906-6705
- Publication type
Article
- DOI
10.1111/j.1600-0625.2012.01520.x