SHARPIN regulates mitochondria-dependent apoptosis in keratinocytes.

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Animals, Apoptosis, Carrier Proteins, Caspases, Cell Proliferation, Dermatitis, Female, Keratinocytes, Membrane Potential, Mitochondrial, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microscopy, Electron, Transmission, Mitochondria, Mutation, Proto-Oncogene Proteins c-bcl-2, bcl-2-Associated X Protein

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J Dermatol Sci 2011 Sep; 63(3):148-53.




BACKGROUND: The chronic proliferative dermatitis mutation (CPDM) in mice, due to Sharpin deficiency (Sharpin(cpdm)), is a multisystem disorder characterized by peripheral blood eosinophilia and eosinophil infiltration of affected tissues including the skin, bone marrow, spleen, lung, heart, and other organs. The epidermis has numerous apoptotic keratinocytes which increase with age, coalesce, form vesicles, and rupture causing ulceration.

OBJECTIVE: To clarify the molecular pathways involved in the keratinocyte apoptosis caused by loss of function of SHARPIN in mice.

METHOD: 10-week-old Sharpin(cpdm) and wildtype mice were used for experiments. Ultrastructural changes of skin were evaluated by transmission electron microscopy. Cross points of mitochondrial pathway were analyzed by in vitro and in vivo cellular and molecular assays.

RESULTS: 77.5% skin cells in Sharpin(cpdm) mice were functionally apoptotic and dead cells, compared to only 18.1% unhealthy skin cells in wildtype mice, indicated by annexin-V/propidium iodide FACS analysis. Mitochondria in keratinocytes were disrupted containing prominent electron dense inclusions and membrane potential depolarization, accompanied by a shift in protein expression between the anti-apoptotic BCL2 and pro-apoptotic BAX proteins. Enzymatic activities of caspases 9 and 3, but not 8, were markedly increased in Sharpin(cpdm) keratinocytes. Caspase-3 was cleaved in most cells in skin of 10-week-old mutant mice.

CONCLUSION: The present results indicated that keratinocyte apoptosis in Sharpin(cpdm) mice was regulated by an intrinsic caspase-dependent mitochondria pathway.

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