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Molecular and Cellular Biology, January 2008, p. 326-332, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01482-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Prevention of Skin Tumorigenesis and Impairment of Epidermal Cell Proliferation by Targeted Aquaporin-3 Gene Disruption{triangledown} ,{dagger}

Mariko Hara-Chikuma and A. S. Verkman*

Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143

Received 16 August 2007/ Returned for modification 26 September 2007/ Accepted 12 October 2007

Aquaporin-3 (AQP3) is a water/glycerol-transporting protein expressed strongly at the plasma membranes of basal epidermal cells in skin. We found that human skin squamous cell carcinoma strongly overexpresses AQP3. A novel role for AQP3 in skin tumorigenesis was discovered using mice with targeted AQP3 gene disruption. We found that AQP3-null mice were remarkably resistant to the development of skin tumors following exposure to a tumor initiator and phorbol ester promoter. Though tumor initiator challenge produced comparable apoptotic responses in wild-type and AQP3-null mice, promoter-induced cell proliferation was greatly impaired in the AQP3-null epidermis. Reductions of epidermal cell glycerol, its metabolite glycerol-3-phosphate, and ATP were found in AQP3 deficiency without impairment of mitochondrial function. Glycerol supplementation corrected the reduced proliferation and ATP content in AQP3 deficiency, with cellular glycerol, ATP, and proliferative ability being closely correlated. Our data suggest involvement of AQP3-facilitated glycerol transport in epidermal cell proliferation and tumorigenesis by a novel mechanism implicating cellular glycerol as a key determinant of cellular ATP energy. AQP3 may thus be an important determinant in skin tumorigenesis and hence a novel target for tumor prevention and therapy.

* Corresponding author. Mailing address: Cardiovascular Research Institute, 1246 Health Sciences East Tower, Box 0521, University of California—San Francisco, San Francisco, CA 94143-0521. Phone: (415) 476-8530. Fax: (415) 665-3847. E-mail: Alan.Verkman{at}ucsf.edu

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2008, p. 326-332, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01482-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Verkman, A. S. (2009). Aquaporins: translating bench research to human disease. J. Exp. Biol. 212: 1707-1715 [Abstract] [Full Text]  


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