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MBC in Press, published online ahead of print August 9, 2006
Mol. Biol. Cell 10.1091/mbc.E06-03-0251

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Submitted on March 30, 2006
Revised on July 18, 2006
Accepted on August 2, 2006

Up-Regulation of TRPC1 following SERCA2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier’s Disease

Biswaranjan Pani,* Eric Cornatzer,* William Cornatzer,{dagger} Dong Min Shin,{ddagger} Mark R. Pittelkow,{sect} Alain Hovnanian,|| Indu S. Ambudkar,¶ and Brij B. Singh*

Departments of *Biochemistry and Molecular Biology and {dagger}Internal Medicine, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202; {ddagger}Department of Oral Biology, Korea 21 Project for Medical Science, Yonsei University College of Dentistry, Seoul 120-752, Korea; {sect}Department of Dermatology, Mayo Clinic College of Medicine, Rochester, MN 55905; ||Department of Functional Genetics of Epithelial Diseases, INSERM U563, 31024 Toulouse Cedex 3, France; Secretory Physiology Section, Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892

Monitoring Editor: M. Bishr Omary

The mechanism(s) involved in regulation of store operated calcium entry in Darier’s disease (DD) is not known. We investigated the distribution and function of TRPC in epidermal skin cells. DD patient’s demonstrated upregulation of TRPC1, but not TRPC3, in the squamous layers. Ca2+ influx was significantly higher in keratinocytes obtained from DD patients and showed enhanced proliferation than normal keratinocytes. Similar upregulation of TRPC1 was also detected in epidermal layers of SERCA2+/- mice. HaCaT cells expressed TRPC1 in the plasma membrane. Expression of SERCA2 si-RNA in HaCaT cells increased TRPC1 levels and thapsigargin-stimulated Ca2+ influx, which was blocked by SOCE inhibitors. Thapsigargin-stimulated intracellular Ca2+ release was decreased in DD cells. DD Keratinocytes exhibited increased cell survival upon thapsigargin treatment. Alternatively, overexpression of TRPC1 or SERCA2-siRNA in HaCaT cells demonstrated resistance to thapsigargin-induced apoptosis. These effects were dependent on external Ca2+ and activation of NF-{kappa}B. Isotretinoin reduced Ca2+ entry in HaCaT cells and decreased survival of HaCaT and DD keratinocytes. These findings put forward a novel consequence of compromised SERCA2 function in DD where upregulation of TRPC1 augments cell proliferation and restrict apoptosis. We suggest that the anti-apoptotic effect of TRPC1 could potentially contribute to abnormal keratosis in DD.

Address correspondence to: Brij B. Singh (bsingh{at}medicine.nodak.edu)




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