Secreted Frizzled-related Protein 1 (SFRP1) Protects Fibroblasts from Ceramide-induced Apoptosis

Secreted frizzled-related proteins (SFRPs) are soluble proteins that have highly restricted tissue distribution. Although not fully understood, a role of SFRP1 in the regulation of apoptosis has been suggested. Our previous study disclosed a much greater level of SFRP1 expression in periodontal ligament fibroblasts (PDLFs), which have been suggested to maintain a reduced level of apoptosis compared with gingival fibroblasts. We have tested the role of SFRP1 in the regulation of fibroblast apoptosis both in vitro and in vivo. Our data showed that SFRP1 was significantly up-regulated in cultured human PDLFs during ceramide-induced apoptosis. In vivo study demonstrated an increased SFRP1 expression in mice periodontal ligament during force-induced apoptosis. While inhibition of endogenous SFRP1 increased the percentage of cell death in cultured human PDLFs, exogenous SFRP1 substantially reduced apoptosis in cultured human gingival fibroblasts, which do not maintain a high level of endogenous SFRP1 expression. The effect of SFRP1 on apoptosis was linked to the regulation of several apoptosis-related genes, including p53, caspase-3, caspase-9, and BCL-2-interacting killer (BIK). Furthermore our results indicated that the addition of exogenous SFRP1 could reduce the level of apoptosis in dermal fibroblasts in vivo, and this effect was also linked to the regulation of similar apoptosis-related genes as observed in in vitro studies. Collectively our results suggest that the constitutive up-regulation of SFRP1 could be an adaptive cell survival mechanism inherent to functionally specialized fibroblasts, and the addition of SFRP1 may contribute to the inhibition of apoptosis in fibroblast-related cells. Secreted frizzled-related proteins (SFRPs) are soluble proteins that have highly restricted tissue distribution. Although not fully understood, a role of SFRP1 in the regulation of apoptosis has been suggested. Our previous study disclosed a much greater level of SFRP1 expression in periodontal ligament fibroblasts (PDLFs), which have been suggested to maintain a reduced level of apoptosis compared with gingival fibroblasts. We have tested the role of SFRP1 in the regulation of fibroblast apoptosis both in vitro and in vivo. Our data showed that SFRP1 was significantly up-regulated in cultured human PDLFs during ceramide-induced apoptosis. In vivo study demonstrated an increased SFRP1 expression in mice periodontal ligament during force-induced apoptosis. While inhibition of endogenous SFRP1 increased the percentage of cell death in cultured human PDLFs, exogenous SFRP1 substantially reduced apoptosis in cultured human gingival fibroblasts, which do not maintain a high level of endogenous SFRP1 expression. The effect of SFRP1 on apoptosis was linked to the regulation of several apoptosis-related genes, including p53, caspase-3, caspase-9, and BCL-2-interacting killer (BIK). Furthermore our results indicated that the addition of exogenous SFRP1 could reduce the level of apoptosis in dermal fibroblasts in vivo, and this effect was also linked to the regulation of similar apoptosis-related genes as observed in in vitro studies. Collectively our results suggest that the constitutive up-regulation of SFRP1 could be an adaptive cell survival mechanism inherent to functionally specialized fibroblasts, and the addition of SFRP1 may contribute to the inhibition of apoptosis in fibroblast-related cells. Apoptosis is a genetically regulated, morphologically distinct form of cell death that plays a major role during development, in homeostasis, and in many diseases (1.Steller H. Science. 1995; 267: 1445-1449Crossref PubMed Scopus (2430) Google Scholar, 2.Golstein P. Science. 1997; 275: 1081-1082Crossref PubMed Scopus (336) Google Scholar). The machinery to carry out apoptosis involves various apoptotic components including the BCL-2 gene family and the caspase gene family (3.Korsmeyer S.J. Shutter J.R. Veis D.J. Merry D.E. Oltvai Z.N. Semin. Cancer Biol. 1993; 4: 327-332PubMed Google Scholar, 4.Ibrado A.M. Huang Y. Fang G. Liu L. Bhalla K. Cancer Res. 1996; 56: 4743-4748PubMed Google Scholar, 5.Boyd J.M. Gallo G.J. Elangovan B. Houghton A.B. Malstrom S. Avery B.J. Ebb R.G. Subramanian T. Chittenden T. Lutz R.J. Chinnadurai G. Oncogene. 1995; 11: 1921-1928PubMed Google Scholar, 6.Tewari M. Quan L.T. O'Rourke K. Desnoyers S. Zeng Z. Beidler D.R. Poirier G.G. Salvesen G.S. Dixit V.M. Cell. 1995; 81: 801-809Abstract Full Text PDF PubMed Scopus (2277) Google Scholar). Studies suggest that apoptosis is regulated by diverse functional pathways, each utilizing a subset of apoptotic genes that are active in different cell types (7.Scaffidi C. Fulda S. Srinivasan A. Friesen C. Li F. Tomaselli K.J. Debatin K.M. Krammer P.H. Peter M.E. EMBO J. 1998; 17: 1675-1687Crossref PubMed Scopus (2628) Google Scholar, 8.van Gijn M.E. Snel F. Cleutjens J.P. Smits J.F. Blankesteijn W.M. Exp. Cell Res. 2001; 265: 46-53Crossref PubMed Scopus (39) Google Scholar). Secreted frizzled-related proteins (SFRPs) 1The abbreviations used are: SFRP, secreted frizzled-related protein; PDLF, periodontal ligament fibroblast; GF, gingival fibroblast; BIK, BCL-2-interacting killer; HRP, horseradish peroxidase; DMEM, Dulbecco's modified Eagle's medium; RT, reverse transcription; RPA, RNase protection assay; BSA, bovine serum albumin; Cer, C2-ceramide; siRNA, small interfering RNA; MTS, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; pNA, p-nitroaniline; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.1The abbreviations used are: SFRP, secreted frizzled-related protein; PDLF, periodontal ligament fibroblast; GF, gingival fibroblast; BIK, BCL-2-interacting killer; HRP, horseradish peroxidase; DMEM, Dulbecco's modified Eagle's medium; RT, reverse transcription; RPA, RNase protection assay; BSA, bovine serum albumin; Cer, C2-ceramide; siRNA, small interfering RNA; MTS, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; pNA, p-nitroaniline; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. are soluble proteins that have a highly restricted tissue distribution (9.Hu E. Zhu Y. Fredrickson T. Barnes M. Kelsell D. Beeley L. Brooks D. Biochem. Biophys. Res. Commun. 1998; 247: 287-293Crossref PubMed Scopus (35) Google Scholar, 10.Uren A. Reichsman F. Anest V. Taylor W.G. Muraiso K. Bottaro D.P. Cumberledge S. Rubin J.S. J. Biol. Chem. 2000; 275: 4374-4382Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, 11.Bafico A. Gazit A. Pramila T. Finch P.W. Yaniv A. Aaronson S.A. J. Biol. Chem. 1999; 274: 16180-16187Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). Studies have indicated that SFRPs are capable of binding to Wnts and frizzled (Fz) receptors to interfere with Wnt signaling, which plays a major role in cell fate determination through the regulation of cell proliferation, differentiation, and apoptosis (12.Cadigan K.M. Nusse R. Genes Dev. 1997; 11: 3286-3305Crossref PubMed Scopus (2227) Google Scholar). Distinctive members of the SFRP family exhibit different expression patterns in vivo, suggesting their ability to modulate diverse aspects of Wnt signaling (13.Bradley L. Sun B. Collins-Racie L. LaVallie E. McCoy J. Sive H. Dev. Biol. 2000; 227: 118-132Crossref PubMed Scopus (54) Google Scholar, 14.Ijiri K. Nagayoshi R. Matsushita N. Tsuruga H. Taniguchi N. Gushi A. Sakakima H. Komiya S. Matsuyama T. J. Rheumatol. 2002; 29: 2266-2270PubMed Google Scholar, 15.Yoshino K. Rubin J.S. Higinbotham K.G. Uren A. Anest V. Plisov S.Y. Perantoni A.O. Mech. Dev. 2001; 102: 45-55Crossref PubMed Scopus (99) Google Scholar). Although the details are far from clear, a prominent role for SFRP1 in the regulation of apoptosis has been suggested (16.Melkonyan H.S. Chang W.C. Shapiro J.P. Mahadevappa M. Fitzpatrick P.A. Kiefer M.C. Tomei L.D. Umansky S.R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13636-13641Crossref PubMed Scopus (289) Google Scholar, 17.Roth W. Wild-Bode C. Platten M. Grimmel C. Melkonyan H.S. Dichgans J. Weller M. Oncogene. 2000; 19: 4210-4220Crossref PubMed Scopus (136) Google Scholar). It has been shown that SFRP1 promotes survival of glioma cells under serum starvation (17.Roth W. Wild-Bode C. Platten M. Grimmel C. Melkonyan H.S. Dichgans J. Weller M. Oncogene. 2000; 19: 4210-4220Crossref PubMed Scopus (136) Google Scholar) and contributes to the development of uterine leiomyomas through an antiapoptotic effect (18.Fukuhara K. Kariya M. Kita M. Shime H. Kanamori T. Kosaka C. Orii A. Fujita J. Fujii S. J. Clin. Endocrinol. Metab. 2002; 87: 1729-1736Crossref PubMed Scopus (58) Google Scholar). It was also suggested that SFRP1 may have proangiogenic effects and appears to protect human umbilical vein endothelial cells from apoptosis in vitro (19.Dufourcq P. Couffinhal T. Ezan J. Barandon L. Moreau C. Daret D. Duplaa C. Circulation. 2002; 106: 3097-3103Crossref PubMed Scopus (93) Google Scholar). Furthermore expression of SFRP1 has been shown to cause spontaneous adipocyte differentiation (20.Bennett C.N. Ross S.E. Longo K.A. Bajnok L. Hemati N. Johnson K.W. Harrison S.D. MacDougald O.A. J. Biol. Chem. 2002; 277: 30998-31004Abstract Full Text Full Text PDF PubMed Scopus (583) Google Scholar), which is known to render adipocytes resistant to apoptotic stimuli (21.Hargrave K.M. Li C. Meyer B.J. Kachman S.D. Hartzell D.L. Della-Fera M.A. Miner J.L. Baile C.A. Obes. Res. 2002; 10: 1284-1290Crossref PubMed Scopus (85) Google Scholar). However, there are also studies suggesting a proapoptotic effect of SFRP1 in breast adenocarcinoma cells (16.Melkonyan H.S. Chang W.C. Shapiro J.P. Mahadevappa M. Fitzpatrick P.A. Kiefer M.C. Tomei L.D. Umansky S.R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13636-13641Crossref PubMed Scopus (289) Google Scholar) and in pulmonary epithelial and endothelial cells (22.Imai K. D'Armiento J. Chest. 2002; 121: 7SAbstract Full Text Full Text PDF PubMed Google Scholar). This leaves the molecular mechanism responsible for the modulation of Wnt signaling and regulation of apoptosis by SFRP1 open to speculation. Indeed SFRP1 has been shown to be a biphasic modulator of Wnt-induced effects different A. Reichsman F. Anest V. Taylor W.G. Muraiso K. Bottaro D.P. Cumberledge S. Rubin J.S. J. Biol. Chem. 2000; 275: 4374-4382Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar). The is an to study cells that of fibroblast differentiation be observed in a periodontal ligament responsible for tissue and M.A. J. Res. 1997; PubMed Scopus Google Scholar, P. C.A. 1996; PubMed Scopus Google Scholar) and gingival responsible for the in the of M. B. R. M. P. H. J. Clin. 2001; PubMed Scopus Google Scholar, A. P. Biol. 1997; PubMed Scopus Google Scholar). Our studies of fibroblast apoptosis in periodontal ligament and gingival that the is an to study the of apoptosis in cells S. J. Res. PubMed Scopus Google Scholar). similar has been used by to study cell death and by in by T. A. M. Y. P. C.A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). periodontal ligament fibroblasts are to exhibit specialized for and of the and A. N. P. E. M. T. J. Clin. 1999; PubMed Scopus Google Scholar, S. S. K. Y. M. T. A. T. H. J. Res. 1999; PubMed Scopus Google Scholar), as as adaptive in in to P. C.A. 1996; PubMed Scopus Google Scholar, U. R. J.M. J. Res. 1998; PubMed Scopus Google Scholar), that cells are to exhibit a reduced level of apoptosis compared with gingival fibroblasts Indeed our study has demonstrated a significantly apoptotic in PDLFs compared with S. J. Res. PubMed Scopus Google Scholar). However, many the in the protection of PDLFs cell apoptosis. our data a significantly level of SFRP1 expression in PDLFs compared with S. J. Res. 2002; 81: PubMed Scopus Google Scholar). However, the role of SFRP1 in the regulation of apoptosis in fibroblasts to be the expression of SFRP1 in PDLFs compared with the of the study was to the role of SFRP1 in the regulation of apoptosis in cell and the of effect on apoptosis. and from and from human SFRP1 was a from Rubin from the of SFRP1 and from was from from Cell PDLFs and cells and as S. J. Res. 2002; 81: PubMed Scopus Google Scholar). the with and by the of In small of gingival and periodontal ligament and cultured in with bovine serum and and in a the cells the and under the the and used for and RNase was from cultured human PDLFs and with to the the of was used as for reverse and was for the of the RPA, and out by the by in vitro in the of to in by RNase for on and with a and in cultured human PDLFs and as M. C. V. L. J. S. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). secreted was and the proteins as J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the from mice was in and with in of and the was and the was with the of proteins on a and to in bovine serum and with and the the of SFRP1 in vivo, tissue in for was by the in for was by with in The for with in and with the for The for with and the with by with of Apoptosis and of in in DMEM, bovine The cells with and in serum bovine Apoptosis was by the addition of was used as a the effects of exogenous SFRP1 on cell human SFRP1 was to the cell the addition of a the of was to the of SFRP1 the effects of endogenous the expression of SFRP1 was by for apoptosis. In the and of small interfering for SFRP1 the the The was the cultured cells The of the are and of Cell and of cultured cells and cultured for different of was each and the for under the in the on a apoptotic cell was by to the cells and cells in the by and The in a different in was by an to the The the of the by from the cells in cell in the the to and was for the of each a with was and the on demonstrated an of by cultured as and was different cells apoptosis in the of exogenous SFRP1 and cells apoptosis with to endogenous SFRP1 expression. with used as of was used in each reverse and was for with for human apoptosis gene The by a and to and the of and as of and was of SFRP1 in Cell of was used to study the of SFRP1 expression during force-induced apoptosis in periodontal mice each The as which not and used as The in which an was the and of the used for tissue and and by the and the of mice with an of and their by with a of and in The in in the and to the of the by was on the of the In of of apoptosis in vivo was terminal deoxynucleotidyl transferase-mediated dUTP nick-end to the each the the cells cells and the of was of SFRP1 during Apoptosis in mice used for a to the effect of SFRP1 on dermal fibroblast apoptosis in vivo. the with a a on the of the the and The and of the by The a The with of this was by a of SFRP1 a of each mice and the with the tissue was in of the tissue was used for and the of was as L. A. L. S. 2002; PubMed Scopus Google Scholar). The of the tissue was in and for and S.D. by and was of SFRP1 in the expression of SFRP1 in cultured human PDLFs and both the and significantly of SFRP1 in PDLFs in different The of SFRP1 also by RPA, a high level of SFRP1 expression in PDLFs compared with results are with our previous data on the of gene expression patterns cultured human PDLFs and S. J. Res. 2002; 81: PubMed Scopus Google Scholar). by the level of SFRP1 was also much in PDLFs in However, the secreted SFRP1 in the was not in PDLFs not results suggest that SFRP1 in PDLFs is not secreted under of SFRP1 during have shown that as are of apoptosis and A. J. Cell. 1998; PubMed Scopus Google Scholar, J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Our data indicated that both PDLFs and apoptosis in a and on to apoptosis as a to study the role of We have the of SFRP1 in cultured PDLFs and apoptosis different by of SFRP1 was observed in PDLFs apoptotic It and a high level However, the level of SFRP1 in was in cells. It showed a small by a an level of and secreted SFRP1 in cultured PDLFs and also by The results showed a of both and secreted SFRP1 in PDLFs apoptosis. This was in the and observed in the and both and secreted SFRP1 This that SFRP1 and is secreted apoptosis. However, showed a level of SFRP1 in cells and a small and of SFRP1 The secreted SFRP1 was in the indicated of SFRP1 during have shown that periodontal ligament cells apoptosis in the of T. M. N. Y. K. H. T. 2001; PubMed Scopus Google Scholar, V. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the SFRP1 expression and the of an force-induced and the apoptosis of periodontal ligament fibroblasts. shown in the apoptotic cells in periodontal ligament The of fibroblasts increased in the periodontal ligament the of and the expression of SFRP1 in the periodontal ligament also increased This apoptotic and a high level This that the expression of SFRP1 the of apoptosis in the periodontal ligament and the role of in vivo, in the regulation of force-induced apoptosis during of SFRP1 on Cell and the effect of exogenous SFRP1 on the regulation of cell and the level of in cultured human PDLFs and apoptosis in the of SFRP1 shown in the percentage of cell survival the in PDLFs in the of exogenous SFRP1 However, the percentage of cell survival increased in the addition of SFRP1 as compared with and The effect of exogenous SFRP1 was also by the of in cultured human PDLFs and The level of was significantly in the addition of SFRP1 as compared with and observed in PDLFs under the This that the constitutive up-regulation of SFRP1 in PDLFs contributes to the inhibition of apoptosis in PDLFs that SFRP1 has In exogenous SFRP1 may have antiapoptotic effects on which do not maintain high of endogenous SFRP1 expression. We also to the SFRP1 and the cultured PDLFs and used in the significantly endogenous SFRP1 expression in PDLFs both and and This with a to study the role of endogenous SFRP1 on the regulation of apoptosis. with for SFRP1 the percentage of cell survival and the level of in cultured PDLFs and apoptosis. The percentage of cell survival was significantly in PDLFs the of SFRP1 expression and and the level was the inhibition of SFRP1 expression and observed in in cell and level of in the of siRNA, to the level of endogenous SFRP1 expression in of endogenous SFRP1 on cell and The expression of SFRP1 was by for as in with for the cell was the in the the level of was by to the The in cell are as S.D. of and as to the with PDLFs and by the effects of of SFRP1 in the regulation of the expression of apoptosis-related genes in cultured human PDLFs and apoptosis a of apoptosis-related genes in PDLFs SFRP1 was by addition of SFRP1 by also genes that in SFRP1 was by addition of SFRP1 shown in observed that the expression of a of apoptosis-related genes was regulated to the SFRP1 was and regulation was in both PDLFs and the addition of SFRP1 gene expression in PDLFs by the inhibition of SFRP1 expression up-regulated the gene expression in PDLFs by Furthermore the of gene was also observed in the addition of SFRP1 data suggest that the antiapoptotic effect of SFRP1 could the regulation of apoptosis-related p53, caspase-3, caspase-9, and genes regulated by addition of SFRP1 inhibition of SFRP1 expression by of gene expression to addition of SFRP1 inhibition of SFRP1 expression by of gene expression to in a of SFRP1 on is the of the effect of SFRP1 on the apoptosis. The addition of SFRP1 active level in cultured human PDLFs the and compared with the this was not In a of was observed in the addition of SFRP1 as compared with the the the SFRP1 gene by a of in PDLFs as as However, there was observed in and for SFRP1 data with the results suggest that the effect of SFRP1 on the of cell survival be through the inhibition of of SFRP1 in our of the role of SFRP1 on the regulation of fibroblast tested the antiapoptotic effect of SFRP1 on a fibroblast dermal fibroblasts. shown in addition of effect on apoptosis as the of cells the compared with the However, the of cells to SFRP1 of SFRP1 showed a inhibition of apoptosis in dermal fibroblasts compared with the the of SFRP1 in the expression of genes shown in by and to the of the to the expression of a gene that was shown to be by the addition of SFRP1 in the results The in the tissue was up-regulated by and the of and SFRP1 as compared with the by in the of a of SFRP1 not reduce this level of expression. level was reduced by the of a of expression was observed SFRP1 was compared with the the of not the expression level of tested proteins for a of expression. Furthermore the effect of SFRP1 on the was also in the The addition of a of SFRP1 effect on In of was the of SFRP1 compared with the of mice different from mice on a and to of the p53, caspase-9, and was in and was with the with and by the for each tissue by and the expression of each was as a to different in cell in the the to and was for the of are as S.D. of to are the cells of the periodontal ligament and the and have in the and tissue of the Although PDLFs and each a functional Our previous study S. J. Res. PubMed Scopus Google Scholar) suggested that PDLFs are to have a of compared with to and specialized for and of the and A. N. P. E. M. T. J. Clin. 1999; PubMed Scopus Google Scholar, S. S. K. Y. M. T. A. T. H. J. Res. 1999; PubMed Scopus Google Scholar) as as adaptive in in to P. C.A. 1996; PubMed Scopus Google Scholar, U. R. J.M. J. Res. 1998; PubMed Scopus Google Scholar). is known the role of SFRP1 in apoptosis of fibroblast-related cells gingival We tested the role of SFRP1 in the regulation of apoptosis in PDLFs both in vitro and in vivo. Our data showed that SFRP1 was a significantly level in cultured human PDLFs compared with during the of apoptosis. In vivo study a the of SFRP1 expression during force-induced apoptosis in periodontal of endogenous SFRP1 expression significantly increased the level of apoptosis in PDLFs, exogenous SFRP1 substantially apoptosis in which do not maintain a high level of endogenous SFRP1 expression. suggest that SFRP1 expression and are for the of cell in PDLFs, and there may be a effect of the endogenous exogenous SFRP1 on the of fibroblast cell apoptosis. SFRP1 has been suggested to interfere with Wnt signaling which gene expression in both and A. Yaniv A. A. Pramila T. M. J. Aaronson S.A. Oncogene. 1999; PubMed Scopus Google Scholar, G. E. L. S. J. R. D.J. 2002; PubMed Scopus Google Scholar), was to that both and effects could be in the inhibition of cell apoptosis. Our data demonstrated that the of SFRP1 to the cell survival in PDLFs may be through the of the proapoptotic BCL-2 genes and and the inhibition of caspase and is a BCL-2 that promotes cell death in a similar to the members of the BCL-2 and J.M. Gallo G.J. Elangovan B. Houghton A.B. Malstrom S. Avery B.J. Ebb R.G. Subramanian T. Chittenden T. Lutz R.J. Chinnadurai G. Oncogene. 1995; 11: 1921-1928PubMed Google Scholar). Although not with cell death is by an B. F. V. L. S. B. K. EMBO J. PubMed Scopus Google Scholar). In with the BCL-2 and and a in the to and caspase B. F. V. L. S. B. K. EMBO J. PubMed Scopus Google Scholar). Indeed our results the of with a of gene in the of Our results also showed a expression of and inhibition of addition of This that SFRP1 may reduce fibroblast apoptosis through the inhibition of caspase and apoptosis C. T. K. T. S. S. A. A. Y. Y. Oncogene. 1997; PubMed Scopus Google Scholar). an up-regulation of gene was observed the addition of SFRP1 during apoptotic on cell by cell Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, B. D. 2000; PubMed Scopus Google Scholar). a of on apoptosis has been suggested. apoptosis the of several genes in the apoptotic of the apoptotic are proapoptotic members of the BCL-2 as and M. J.P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). the have demonstrated a of gene by p53, as which is as a and apoptosis through Fang L. M. T. Aaronson S.A. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, L. Li G. Liu G. Aaronson S.A. EMBO J. 2001; PubMed Scopus Google Scholar). The observed of and by SFRP1 that the up-regulation of not to the of apoptotic is the by BCL-2 which was observed to be up-regulated in the of Studies have shown that BCL-2 is in the determination of survival apoptosis and the C. S. B. Oncogene. 1997; PubMed Scopus Google Scholar, V. F. C. N. P. V. B. J.L. Biochem. Biophys. Res. Commun. 2002; PubMed Scopus Google Scholar). up-regulation of BCL-2 by SFRP1 could the apoptotic the of BCL-2 the apoptotic a that is resistant to was to that up-regulation of could be an mechanism for cell survival during However, the effect of up-regulation of on to be In data from the the antiapoptotic effect of SFRP1 on dermal fibroblasts during apoptotic This our of the role of SFRP1 on the regulation of apoptosis in fibroblast SFRP1 is as an cell survival for of mechanism could the development of for tissue and this study on the of fibroblast suggesting that SFRP1 contributes to the reduced level of fibroblast apoptosis through the regulation of p53, and of including of SFRP1 inhibition of endogenous SFRP1 could be a to and tissue by cell We are to Rubin for the with