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

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. 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. Hereditary gingival fibromatosis (HGF) 2The abbreviations used are: HGF, hereditary gingival fibromatosis; CCNE1, cyclin E1; CCNE2, cyclin E2; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; PCNA, proliferation cell nuclear antigen; Rb, retinoblastoma tumor suppressor protein; pRB, phospho-Rb; SOS1, Son of Sevenless-1; GEF, guanine nucleotide exchange factor; MEK, MAPK/ERK kinase; HA, hemagglutinin; TRITC, tetramethylrhodamine isothiocyanate; TFDP1, -2, transcription factors DP1 and -2; TBP, TATA-box-binding protein; siRNA, small interference RNA. 2The abbreviations used are: HGF, hereditary gingival fibromatosis; CCNE1, cyclin E1; CCNE2, cyclin E2; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; PCNA, proliferation cell nuclear antigen; Rb, retinoblastoma tumor suppressor protein; pRB, phospho-Rb; SOS1, Son of Sevenless-1; GEF, guanine nucleotide exchange factor; MEK, MAPK/ERK kinase; HA, hemagglutinin; TRITC, tetramethylrhodamine isothiocyanate; TFDP1, -2, transcription factors DP1 and -2; TBP, TATA-box-binding protein; siRNA, small interference RNA. is a genetic condition characterized by a slowly progressive, benign fibrous enlargement of keratinized gingiva (1Gorlin R.J. Cohen Jr., M.M. Levi L.S. Syndromes of the Head and Neck. 4th Ed. Oxford University Press, New York2001: 847-857Google Scholar, 2Hart T.C. Pallos D. Bowden D.W. Bolyard J. Pettenati M.J. Cortelli J.R. Am. J. Hum. Genet. 1998; 62: 876-883Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 3Witkop Jr., C.J. Birth Defects Orig. Artic Ser. 1971; 7: 210-221PubMed Google Scholar). Genetic studies demonstrate locus heterogeneity for HGF, but etiologic mutations have only been identified in the Son of Sevenless-1 gene (SOS1) (4Hart T.C. Zhang Y. Gorry M.C. Hart P.S. Cooper M. Marazita M.L. Marks J.M. Cortelli J.R. Pallos D. Am. J. Hum. Genet. 2002; 70: 943-954Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). An SOS1 g.126,142–126,143insC insertion mutation causes a frameshift and early termination of the protein, yielding a chimeric 1,105-amino acid protein that consists of 1,083 SOS1 N-terminal amino acids followed by 22 novel amino acids. This truncation abolishes four C-terminal proline-rich motifs, which are required for Grb2 binding. The form of HGF due to SOS1 mutation is designated HGF1. SOS1 functions as a guanine nucleotide exchange factor (GEF) that couples receptor tyrosine kinases to the Ras signaling pathway and controls cell proliferation, differentiation, vesicle trafficking, and regulation of the actin cytoskeleton (5Marshall M.S. Trends Biochem. Sci. 1993; 18: 250-254Abstract Full Text PDF PubMed Scopus (194) Google Scholar). Under the control of two classes of regulatory proteins, GEF and GTPase-activating proteins, Ras functions as a molecular switch between GDP/GTP cycling (6Bourne H.R. Sanders D.A. McCormick F. Nature. 1991; 348: 125-132Crossref Scopus (1836) Google Scholar). Three Ras-GEFs; SOS, guanine nucleotide-releasing factor, and guanyl nucleotide-releasing protein, have been characterized in controlling Ras activation by catalyzing GDP release and association with GTP (7Bar-Sagi D. Hall A. Cell. 2000; 103: 227-238Abstract Full Text Full Text PDF PubMed Scopus (702) Google Scholar, 8Campbell S.L. Khosravi-Far R. Rossman K.L. Clark G.J. Der C.J. Oncogene. 1998; 17: 1395-1413Crossref PubMed Scopus (919) Google Scholar, 9Reuther G.W. Der C.J. Curr Opin Cell Biol. 2000; 2: 157-165Crossref Scopus (346) Google Scholar, 10Egan S.E. Giddings B.W. Brooks M.W. Buday L. Sizeland A.M. Weinberg R.A. Nature. 1993; 363: 45-51Crossref PubMed Scopus (1008) Google Scholar, 11Khosravi-Far R. Der C.J. Cancer Metastasis Rev. 1994; 13: 67-89Crossref PubMed Scopus (310) Google Scholar). Two regulatory regions govern the GEF activity of SOS1: a catalytic site that interacts with nucleotide-free Ras and an allosteric site that enhances exchange activity with the binding of nucleotide-Ras (12Hoffman G.R. Cerione R.A. FEBS Lett. 2002; 513: 85-91Crossref PubMed Scopus (117) Google Scholar, 13Margarit S.M. Sondermann H. Hall B.E. Nagar B. Hoelz A. Pirruccello M. Bar-Sagi D. Kuriyan J. Cell. 2003; 112: 685-695Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar). Upon activation of receptor tyrosine kinase, Grb2-SOS1 complexes are recruited to the plasma membrane leading to the exchange of GDP for GTP and Ras activation (14Chardin P. Camonis J.H. Gale N.W. Van Aelst L. Schlessinger J. Wigler M.H. Bar-Sagi D. Science. 1993; 260: 1338-1343Crossref PubMed Scopus (657) Google Scholar). Although the Grb2-SOS1 complex functions exclusively as an Ras activator, SOS1 can also function as a GEF that is specific to the GTPase Rac1. These two distinct catalytic functions of SOS1 are mutually exclusive and reciprocally related (7Bar-Sagi D. Hall A. Cell. 2000; 103: 227-238Abstract Full Text Full Text PDF PubMed Scopus (702) Google Scholar). The activation of Ras signal stimulates downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) family, a ubiquitous signal transduction pathway (15Schlessinger J. Bar-Sagi D. Cold Spring Harbor Symp. Quant. Biol. 1994; 59: 173-179Crossref PubMed Scopus (89) Google Scholar, 16Schaeffer H.J. Weber M.J. Mol. Cell. Biol. 1999; 19: 2435-2444Crossref PubMed Scopus (1401) Google Scholar). Differences in the duration, intensity, spatial distribution, and temporal qualities of ERK signaling govern distinct biological responses (17Murphy L.O. Smith S. Chen R.H. Fingar D.C. Blenis J. Nat. Cell Biol. 2002; 4: 556-564Crossref PubMed Scopus (759) Google Scholar, 18Murphy L.O. MacKeigan J.P. Blenis J. Mol. Cell. Biol. 2004; 24: 144-153Crossref PubMed Scopus (268) Google Scholar, 19Murphy L.O. Blenis J. Trends Biochem. Sci. 2006; 31: 268-275Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar). For example, transient induction of ERK signaling by EGF leads to proliferation of PC12 cells, whereas sustained signaling induces differentiation (20Gotoh Y. Nishida E. Yamashita T. Hoshi M. Kawakami M. Sakai H. Eur. J. Biochem. 1990; 193: 661-669Crossref PubMed Scopus (322) Google Scholar, 21Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4230) Google Scholar, 22Nguyen T.T. Scimeca J.C. Filloux C. Peraldi P. Carpentier J.L. Van Obberghen E. J. Biol. Chem. 1993; 268: 9803-9810Abstract Full Text PDF PubMed Google Scholar, 23Traverse S. Seedorf K. Paterson H. Marshall C.J. Cohen P. Ullrich A. Curr. Biol. 1994; 4: 694-701Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar, 24Cowley S. Paterson H. Kemp P. Marshall C.J. Cell. 1994; 77: Full Text PDF PubMed Scopus Google Scholar, J.M. S. K. Science. 1994; PubMed Scopus Google Scholar). to extracellular stimuli, signaling control of cell cycle of ERK from the to the is for activation and of and These transcription factors the expression of as cyclin and which are for the progression from G1 to S A. D. P. S. S. J. J. 1999; 18: PubMed Scopus Google Scholar, P. J.M. A. J. J. Cell Biol. 1998; PubMed Scopus Google Scholar). cell proliferation been for gingival fibroblasts in and Pallos D. J. Hart T.C. J. 2006; PubMed Scopus Google Scholar). we that mutant SOS1 an increased and sustained activation of ERK signaling in fibroblasts ERK signaling leads to increased expression of cell cycle and transcription factors. RNA SOS1 depletion was used to the association between SOS1 ERK and gingival fibroblast These findings a SOS1 mutation and a molecular for gingival overgrowth in HGF1. of and Cell gingival with from and of the SOS1 g.126,142–126,143insC Three of gingival fibroblasts from and controls and in and in a and to Pallos D. J. Hart T.C. J. 2006; PubMed Scopus Google Scholar). from and human SOS1 expression was a from D. Bar-Sagi University of New The control was by to release the and The was used with to the that the mutation and The mutation was by For transient in a gingival fibroblasts by was and J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus (79) Google Scholar). the of SOS1, in of expression and the Cell and Ras proliferation of gingival fibroblasts in the growth was with for The was with growth and for from and the cell was by a Ras in to and for with EGF for in and Ras activity was a Ras For of cell was with Ras binding for The complexes by and with and complexes with by and to a by and and the of the in growth to for of EGF with and with to the of EGF as with and by of nuclear and as J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus (79) Google Scholar). with with the with a with and from signal-regulated kinase and from by and to and a and of for was as A. K. J. Cell Sci. PubMed Scopus Google Scholar). gingival fibroblasts in growth for and with for with for the with with for the cell with for and with and RNA from cell of control and fibroblast in for to growth for by and the RNA and a as M. T. K. K. J. Cell Sci. 1999; 112: PubMed Google with and from These SOS1 transcription factor DP1 transcription factor cyclin and cyclin The TATA-box-binding protein was used as control for RNA was used as a in levels of the in as with RNA and RNA of SOS1 the insertion with the as A. K. J. Cell Sci. PubMed Scopus Google Scholar). of gingival fibroblasts in with SOS1 expression was by The for A. H. Nat. 2002; PubMed Scopus Google was used as a and to the of proliferation, fibroblasts with and with growth the of was as with gene expression in to EGF and fibroblast for and with EGF for RNA from and was as The RNA was with The RNA with cell cycle and the expression levels of gene with a to and signal by the with of and with of and of proliferation and of the was used to the between and of of SOS1 in insertion mutation of SOS1 in in an early termination as in the of truncated SOS1 in with the the N-terminal of SOS1 in controls and two and in The to the SOS1 and the the molecular of the truncated mutant expression of wild-type and mutant SOS1 gingival in the type and and mutant and the as the and and truncated SOS1 and the of the mutant was the in The of mutant SOS1 could from the of protein to the of wild-type and mutant SOS1 in levels of SOS1 in fibroblasts in control fibroblasts The as an The levels of mutant SOS1 protein in fibroblasts a mutant SOS1 of controls and only from of control and fibroblasts are of in SOS1 a in the signaling pathway T.T. Scimeca J.C. Filloux C. Peraldi P. Carpentier J.L. Van Obberghen E. J. Biol. Chem. 1993; 268: 9803-9810Abstract Full Text PDF PubMed Google the of the SOS1 mutation Ras signaling was Although Ras activity was in control increased EGF and levels by Ras activity was in HGF1. Upon EGF Ras activity in fibroblasts levels control in mutant SOS1 leading to Ras activity in to growth factor the SOS1 mutation signal transduction through the MAPK/ERK in a transient activation of with of EGF in a increase in control and The magnitude of activation was in in control fibroblasts of EGF cells, whereas the signal was but only in the signal in in control fibroblasts These Ras and leads to a sustained activation of signal in of by EGF was in the of the and M. T. K. K. J. Cell Sci. 1999; 112: PubMed Google Scholar, L. T. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). The of in a of signal in cell The in in control fibroblasts The duration of ERK activation was through the induction of the of EGF, the signal increased and the in cell The signal to levels Although the of to EGF induction was in cell the was in in control fibroblasts The of the duration of ERK signaling is in of ERK signaling was in the of in cell the of was in with control with of in control whereas of in The signal was sustained to in but in control to levels in levels of ERK signal in These demonstrate in the of growth Ras with downstream signaling and sustained in induction by EGF a in magnitude and duration, the of the SOS1 mutation in of SOS1 in binding of growth factors to their the of the complex from the to plasma membrane H. C. A. A. Ullrich A. J. PubMed Scopus Google we the of SOS1 in the SOS1 was found in and membrane with only of mutant SOS1 in the membrane This is due to the expression of the mutant SOS1 in fibroblasts the and truncated SOS1 in cells, which have gingival fibroblasts Under of SOS1 was in the whereas of truncated SOS1 was found in The which only SOS1, of SOS1 was in the and with and The of the found in the and These demonstrate the of is for truncated SOS1 in the growth wild-type and mutant SOS1 in the and membrane a and in whereas wild-type SOS1 in the mutant SOS1 in the and plasma membrane These by the the of SOS1 in fibroblasts These in the of growth truncated SOS1 in the plasma membrane the SOS1 to ERK in the of mutant SOS1 leads to increased ERK signaling, SOS1 expression gingival and ERK was of of the mutant SOS1 control fibroblasts in a increase of ERK signaling of signal in fibroblasts with truncated with wild-type and of in fibroblasts to fibroblasts with mutant and These that the of mutant SOS1 leads to levels of signal in gingival Selective of and SOS1 by interference to the mutant SOS1 ERK signaling and fibroblast the specific mutant the to the mutation Three of to the with downstream the mutation site and the and of siRNA, the with SOS1 expression of SOS1 was in levels of SOS1 may SOS1, was to that in the control and wild-type SOS1 and for the whereas have of wild-type SOS1 the of truncated SOS1 the and with controls and and of the truncated The was to the wild-type SOS1 and was to mutant due to wild-type the of with wild-type mutant SOS1 expression the of wild-type SOS1 was as the of was of was mutant SOS1 was as as of was used These demonstrate that RNA could and the truncated SOS1 with the The of and SOS1 and ERK signaling are in and mutant SOS1 and by Although the the of a the mutant SOS1 with depletion The of SOS1 through the of signaling and fibroblasts ERK signaling was and a in with of in signal observed was only of the signal with the control was used in by was due to depletion of mutant SOS1 the wild-type SOS1 the signal as the of increased mutant SOS1 to sustained signaling in These demonstrate that can mutant with wild-type of SOS1 in the of SOS1 depletion gingival fibroblast proliferation, fibroblasts with the and cell proliferation was of control fibroblasts with with controls cell Although cell increased and the of fibroblasts was the control the growth of control fibroblasts and used the in cell proliferation was with the with Although depletion of wild-type SOS1 the proliferation of control cell proliferation to the the was for fibroblasts in the of cell proliferation also of wild-type SOS1 in in cell proliferation with control fibroblasts from to was observed by of mutant SOS1 in a in cell proliferation with the cell growth and as for the wild-type SOS1 fibroblasts with and cell proliferation and and with the control These of the mutant SOS1 proliferation of fibroblasts and of mutant SOS1 a of fibroblast proliferation the of wild-type These findings mutant SOS1 is responsible for the increase of fibroblast proliferation in HGF1. of Cell in ERK signaling in fibroblasts is associated with cell cycle control M. J.C. Aelst L. M. 1998; PubMed Scopus Google Scholar, M. D. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). ERK signaling cell cycle progression in gingival we used a in cell cycle Under and control fibroblasts sustained and transient ERK signaling, the of transient sustained ERK signaling the expression of cell cycle regulators, two control fibroblasts and control in 1, a increase in control fibroblasts in the cell cycle progression and for G1 and from G1 S the increase in expression was in the control in the control for cyclins C, and and Although the transcription factors and increased their DP1 and and These in cell cycle regulation to that may downstream of the sustained ERK signaling in of sustained transient ERK signaling the expression of cell cycle of EGF and of EGF and of between two is in transcription factor transcription factor cell nuclear binding protein factor factor The of EGF and of between two is in in a the findings and and complexes are to promote cell cycle from G1 S in A. A. D. Yamashita K. S. T. J.M. Science. PubMed Scopus Google Scholar, Weinberg R.A. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar). gingival fibroblasts in fibroblasts in controls and to growth a was in cell and the was in fibroblasts and sustained signaling in fibroblasts in of cyclin was in in control fibroblasts with found in control and fibroblasts in growth cyclin expression was in fibroblasts in control fibroblasts to growth levels of cyclin increased and in control and cyclin levels in in control fibroblasts growth cyclin a in the overgrowth of HGF1. of TFDP1, and also activation of the is the for cell cycle progression from G1 S Under levels for control and fibroblasts and to growth expression increased in control and the levels of in of fibroblasts expression levels in in control fibroblasts in and growth found for expression between the two of from to growth in cell that cyclin and a in cell cycle regulation in gingival fibroblasts and the cell cycle is in fibroblasts in control fibroblasts and may underlie the proliferation in of the gene by ERK signaling is the early growth gene P. R. P. Sci. S. A. PubMed Scopus Google Scholar). Under of Egr-1 in control fibroblasts whereas levels of Egr-1 found in fibroblasts to growth Egr-1 levels increased in control and fibroblasts and Egr-1 levels in HGF1. The of Egr-1 and PCNA, for cell proliferation, in fibroblasts with controls levels of Egr-1 and in the of with and with the control of Egr-1 and and used These are with the that ERK signal was observed in the by by in fibroblasts These that sustained ERK signaling leads to the up-regulation of that promote cell cycle progression from G1 to S in we have the of gingival overgrowth in with SOS1 studies demonstrate that the of SOS1 is in fibroblasts the mutant is the wild-type Although the of wild-type SOS1 to the mutant in fibroblasts mutant by of cell proliferation that the increased proliferation of fibroblasts was the function of mutant the and the C-terminal are in of activity S. S.M. D. Bar-Sagi D. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar). SOS1 the C-terminal and to the plasma membrane increased GEF activity and the Ras signaling without A. Bar-Sagi D. Sci. 2002; Scholar, L. J. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, A. D. Schlessinger J. M. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, L. L. A. Science. 1995; 268: PubMed Scopus Google Scholar, J.M. E. J. S.E. Nat. 1995; PubMed Scopus Google Scholar). without growth factors stimuli, we observed the truncated SOS1 in the Although the that mutant SOS1 could with of SOS1 and SOS1 that mutant protein could to the plasma membrane in The for the is that the novel 22 C-terminal from the frameshift mutation a in membrane to protein to the plasma membrane SOS1 mutations found in T. L. Y. A.M. Nat. Genet. PubMed Scopus Google Scholar, M. C. A. B. K. S. A. J. J. C. F. C. K. C.J. J.P. M.C. B. Bar-Sagi D. Nat. Genet. PubMed Scopus Google are in the of SOS1 and to of Ras the truncation mutation abolishes the C-terminal proline-rich and could also release the of SOS1 in fibroblasts is of sustained activation of Ras/MAPK signaling in the of growth factors of ERK signaling was by mutant SOS1 was in the plasma membrane, to sustained activation of Ras signaling. The of also but ERK signaling. These findings that mutant SOS1 may ERK signaling through that their to the kinase through an in of the pathway that in sustained ERK activation with tumor Y. T. H. K. H. Y. M. K. Y. S. Y. Nat. Genet. PubMed Scopus Google Scholar, C. J.M. M. J. E. Oncogene. Google Scholar). activity in fibroblasts and tumor in by C-terminal truncated of SOS1 A. D. Schlessinger J. M. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, L. L. A. Science. 1995; 268: PubMed Scopus Google Scholar, M. A. A. L. J. Schlessinger J. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is that the activity used in levels of mutant protein which leads to ERK signaling and a of expression to that the benign form of overgrowth in can as the of SOS1 mutant with release from could in sustained activation with ERK which is to to proliferation but to of the in the pathway as Ras and in sustained signaling and cell growth M.L. Cell. 2000; 103: Full Text Full Text PDF PubMed Scopus Google Scholar, D.A. Marshall C.J. S.M. 7: Full Text Full Text PDF PubMed Scopus Google Scholar). we sustained transient with ERK signaling in gingival the expression of cyclin C, D, and E in fibroblasts cyclin are the downstream of the sustained ERK signaling. the expression of cyclin is in and in J.M. M. S. Chen E. M. S. Mol. Cell. Biol. 1999; 19: PubMed Google Scholar). found that levels of cyclin increase in cell switch cyclin a in from G1 to S in gingival fibroblasts and also a in the control of cell cycle progression 1998; PubMed Scopus Google Scholar, J.R. Hum. Mol. Genet. PubMed Scopus Google Scholar). complexes to and J.M. M. S. Chen E. M. S. Mol. Cell. Biol. 1999; 19: PubMed Google Scholar). Upon of Rb, the complex is and their downstream J. A. L. J.R. Sci. S. A. PubMed Scopus Google Scholar). observed levels of in fibroblasts and growth fibroblasts to growth and and increased and is that a in cell cycle control in to the sustained ERK transient and sustained activation of ERK expression of as and only sustained ERK signaling leads to phosphorylation and of (17Murphy L.O. Smith S. Chen R.H. Fingar D.C. Blenis J. Nat. Cell Biol. 2002; 4: 556-564Crossref PubMed Scopus (759) Google Scholar, 18Murphy L.O. MacKeigan J.P. Blenis J. Mol. Cell. Biol. 2004; 24: 144-153Crossref PubMed Scopus (268) Google Scholar). observed that the increase of Egr-1 expression in and the depletion of wild-type mutant SOS1, the of Egr-1 and PCNA, of the of the complex The findings in a function of mutant SOS1 and a for fibroblast proliferation SOS1 mutations in gingival overgrowth was T. L. Y. A.M. Nat. Genet. PubMed Scopus Google Scholar, M. C. A. B. K. S. A. J. J. C. F. C. K. C.J. J.P. M.C. B. Bar-Sagi D. Nat. Genet. PubMed Scopus Google the truncated SOS1 in in gingival is SOS1 mutations in The SOS1 insertion mutation in in a chimeric protein, whereas the mutations are mutations that a amino the overgrowth of is to gingival four of SOS1 have been in and cell C. J.M. M. J. E. Oncogene. Google Scholar). have observed two SOS1 and in gingival with the of which an C-terminal that are in J.M. C. P. J. E. Oncogene. Google is to the observed in the early termination of SOS1 of the acid and is that specific complexes with their may in gingival fibroblasts and to the gingival the SOS1 mutation in to a of function that an increase in gingival fibroblast a and to the signaling pathway and biological in a and the of RNA interference depletion of SOS1 also a for controlling the gingival are to University of New for the human and M. for of the also for with