Consequences of Depleted SERCA2-Gated Calcium Stores in the Skin

Sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) pumps belong to the family of Ca2+-ATPases responsible for the maintenance of calcium in the endoplasmic reticulum. In epidermal keratinocytes, SERCA2-controled calcium stores are involved in cell cycle exit and onset of terminal differenti...

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Published in:	Journal of investigative dermatology 2006-04, Vol.126 (4), p.721-731
Main Authors:	Müller, Eliane J., Caldelari, Reto, Kolly, Carine, Williamson, Lina, Baumann, Dominique, Richard, Gabriele, Jensen, Pamela, Girling, Peter, Delprincipe, Franco, Wyder, Marianne, Balmer, Vreni, Suter, Maja M.
Format:	Article
Language:	eng
Subjects:	Animals Blister - genetics Blister - pathology Calcium-Transporting ATPases - genetics Cell Adhesion Cell Cycle Cell Differentiation - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Darier Disease - genetics Darier Disease - pathology Dogs Endoplasmic Reticulum - metabolism Epidermis - chemistry Epidermis - pathology Humans Intercellular Junctions - genetics Keratinocytes - chemistry Keratinocytes - pathology Ki-67 Antigen - analysis Male Mutation Phenotype Sarcoplasmic Reticulum Calcium-Transporting ATPases Up-Regulation
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Summary:	Sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) pumps belong to the family of Ca2+-ATPases responsible for the maintenance of calcium in the endoplasmic reticulum. In epidermal keratinocytes, SERCA2-controled calcium stores are involved in cell cycle exit and onset of terminal differentiation. Hence, their dysfunction was thought to provoke impaired keratinocyte cohesion and hampered terminal differentiation. Here, we assessed cultured keratinocytes and skin biopsies from a canine family with an inherited skin blistering disorder. Cells from lesional and phenotypically normal areas of one of these dogs revealed affected calcium homeostasis due to depleted SERCA2-gated stores. In phenotypically normal patient cells, this defect compromised upregulation of p21WAF1 and delayed the exit from the cell cycle. Despite this abnormality it failed to impede the terminal differentiation process in the long term but instead coincided with enhanced apoptosis and appearance of chronic wounds, suggestive of secondary mutations. Collectively, these findings provide the first survey on phenotypic consequences of depleted SERCA-gated stores for epidermal homeostasis that explain how depleted SERCA2 calcium stores provoke focal lesions rather than generalized dermatoses, a phenotype highly reminiscent of the human genodermatosis Darier disease.
ISSN:	0022-202X 1523-1747