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J. Biol. Chem., Vol. 282, Issue 28, 20245-20255, July 13, 2007

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Germ Line Gain of Function with SOS1 Mutation in Hereditary Gingival Fibromatosis^*

Shyh-Ing Jang, Eun-Jin Lee, P. Suzanne Hart, Mukundhan Ramaswami, Debora Pallos^¶, and Thomas C. Hart¹

From the Section of Human and Craniofacial Genetics, NIDCR, National Institutes of Health (NIH), Bethesda, Maryland 20892, the Office of the Clinical Director, NHGRI, NIH, Bethesda, Maryland 20892, and the ^¶Periodontics Research and Graduate Studies Division, Department of Dentistry, University of Taubate, Sao Paulo 12020-270, Brazil

Mutation of human SOS1 is responsible for hereditary gingival fibromatosis type 1, a benign overgrowth condition of the gingiva. Here, we investigated molecular mechanisms responsible for the increased rate of cell proliferation in gingival fibroblasts caused by mutant SOS1 in vitro. Using ectopic expression of wild-type and mutant SOS1 constructs, we found that truncated SOS1 could localize to the plasma membrane, without growth factor stimuli, leading to sustained activation of Ras/MAPK signaling. Additionally, we observed an increase in the magnitude and duration of ERK signaling in hereditary gingival fibromatosis gingival fibroblasts that was associated with phosphorylation of retinoblastoma tumor suppressor protein and the up-regulation of cell cycle regulators, including cyclins C, D, and E and the E2F/DP transcription factors. These factors promote cell cycle progression from G₁ to S phase, and their up-regulation may underlie the increased gingival fibroblast proliferation observed. Selective depletion of wild-type and mutant SOS1 through small interfering RNA demonstrates the link between mutation of SOS1, ERK signaling, cell proliferation rate, and the expression levels of Egr-1 and proliferating cell nuclear antigen. These findings elucidate the mechanisms for gingival overgrowth mediated by SOS1 gene mutation in humans.

Received for publication, February 23, 2007 , and in revised form, May 14, 2007.

^* This work was supported from the intramural Research Program of the NIDCR, National Institutes of Health (to T. C. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Section of Human and Craniofacial Genetics, NIDCR, National Institutes of Health, Rm. 5-2531, Bldg. 10, 10 Center Drive, Bethesda, MD 20892. Tel.: 301-451-8994; Fax: 301-480-4455; E-mail: thart{at}mail.nih.gov.

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