Germ line gain of function with SOS1 mutation in hereditary gingival fibromatosis

被引:31
作者
Jang, Shyh-Ing
Lee, Eun-Jin
Hart, P. Suzanne
Ramaswami, Mukundhan
Pallos, Debora
Hart, Thomas C.
机构
[1] NIH, NIDCR, Sect Human & Craniofacial Genet, Bethesda, MD 20892 USA
[2] NHGRI, NIH, Bethesda, MD 20892 USA
[3] Univ Taubate, Dept Dent, Periodont Res & Grad Studies Div, BR-12020 Sao Paulo, Brazil
关键词
D O I
10.1074/jbc.M701609200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:20245 / 20255
页数:11
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