title: Germ line gain of function with SOS1 mutation in hereditary gingival fibromatosis.
abstract: 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 G(1) 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.
authors.affiliation: Section of Human and Craniofacial Genetics, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Shyh-Ing
authors.initials: SI
authors.lastname: Jang
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Lee
authors.forename: P Suzanne
authors.initials: PS
authors.lastname: Hart
authors.forename: Mukundhan
authors.initials: M
authors.lastname: Ramaswami
authors.forename: Debora
authors.initials: D
authors.lastname: Pallos
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Hart
mesh_terms: D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016213:Cyclins / Q000096:biosynthesis; D050684:E2F Transcription Factors / Q000096:biosynthesis; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005351:Fibromatosis, Gingival / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016193:G1 Phase / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D020837:SOS1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016213:Cyclins; D050684:E2F Transcription Factors; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D020837:SOS1 Protein; D048049:Extracellular Signal-Regulated MAP Kinases