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J. Biol. Chem., Vol. 280, Issue 7, 5870-5874, February 18, 2005

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Transgenic Expression of Dominant Negative Tuberin through a Strong Constitutive Promoter Results in a Tissue-specific Tuberous Sclerosis Phenotype in the Skin and Brain^*

Baskaran Govindarajan, Daniel J. Brat¶, Marie Csete||, William D. Martin¶, Emma Murad, Karin Litani, Cynthia Cohen¶, Francesca Cerimele, Matthew Nunnelley, Benjamin Lefkove, Toshiyuki Yamamoto**, Chunsik Lee, and Jack L. Arbiser¶¶

From the Departments of Dermatology, ^¶Pathology, and ^||Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, ^**Rudbeck Laboratory, Department of Dermatology, Tokyo Medical and Dental University, School of Medicine, 1-5-45 Bunkyo-ku, Tokyo 113-8519, Japan, the Department of Genetics and Pathology, Uppsala University, S-751 85 Uppsala, Sweden, and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia 30322

Tuberous sclerosis (TS) is a common autosomal dominant disorder caused by loss or malfunction of hamartin (tsc1) or tuberin (tsc2). Many lesions in TS do not demonstrate loss of heterozygosity for these genes, implying that dominant negative forms of these genes may account for some hamartomas and neoplasms in TS. To test this hypothesis, we expressed a dominant negative allele of tuberin (RG) behind the cytomegalovirus promoter in NIH3T3 cells and transgenic mice. This allele binds hamartin but has a deletion in the C terminus of tuberin, leading to constitutive activation of rap1 and rab5/rabaptin. Expression of RG in NIH3T3 cells led to a strong induction of reactive oxygen species, induction of vascular endothelial growth factor, and malignant transformation in vivo. Expression of RG driven by the constitutive cytomegalovirus promoter led to high level expression in all murine tissues examined, including skin, kidney, liver, and brain. Surprisingly, mice expressing the RG transgene developed a fibrovascular collagenoma in the dermis, which closely resembles the Shagreen patch observed in human patients with TS. In addition, numerous small subpial collections of external granule cells in the cerebellum were observed, which may be the murine equivalent of subependymal giant cell astrocytomas or tubers commonly seen in TS patients. Thus, expression of a dominant negative tuberin in multiple tissues can lead to a tissue-specific phenotype resembling some of the findings in human TS. Our data are the first to demonstrate that specific signaling abnormalities underlie specific hamartomas in a model of a human genetic disorder.

Received for publication, October 15, 2004 , and in revised form, November 24, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Dermatology Foundation Career Development Award.

Supported by the Tuberous Sclerosis Alliance and Grant RO1 AR47901 from the National Institutes of Health. To whom correspondence should be addressed: Dept. of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Dr., Atlanta, GA 30322. Tel.: 404-727-5063; Fax: 404-727-0923; E-mail: jarbise{at}emory.edu.

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