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Vol. 17, Issue 10, 4446-4458, October 2006

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Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease

Biswaranjan Pani^*, Eric Cornatzer^*, William Cornatzer, Dong-Min Shin, Mark R. Pittelkow, Alain Hovnanian^||, Indu S. Ambudkar^¶, and Brij B. Singh^*

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

Submitted March 30, 2006; Revised July 18, 2006; Accepted August 2, 2006
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 transient receptor potential canonical (TRPC) in epidermal skin cells. DD patients demonstrated up-regulation of TRPC1, but not TRPC3, in the squamous layers. Ca²⁺ influx was significantly higher in keratinocytes obtained from DD patients and showed enhanced proliferation compared with normal keratinocytes. Similar up-regulation of TRPC1 was also detected in epidermal layers of SERCA2^+/– mice. HaCaT cells expressed TRPC1 in the plasma membrane. Expression of sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA)2 small interfering RNA (siRNA) in HaCaT cells increased TRPC1 levels and thapsigargin-stimulated Ca²⁺ influx, which was blocked by store-operated calcium entry 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 nuclear factor-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 wherein up-regulation 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)

Abbreviations used: DD, Darier's disease; SERCA, sarco(endo)plasmic reticulum Ca²⁺ ATPase; SOCE, store operated calcium entry; Tg, thapsigargin; TRPC1, transient receptor potential canonical 1.

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