CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts.
CCN2 is induced by transforming growth factor-beta (TGFbeta) in fibroblasts and is overexpressed in connective tissue disease. CCN2 has been proposed to be a downstream mediator of TGFbeta action in fibroblasts; however, the role of CCN2 in regulating this process unclear. By using embryonic fibrobl...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2006
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| _version_ | 1797088559921889280 |
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| author | Shi-wen, X Stanton, L Kennedy, L Pala, D Chen, Y Howat, S Renzoni, E Carter, D Bou-Gharios, G Stratton, R Pearson, J Beier, F Lyons, K Black, C Abraham, D Leask, A |
| author_facet | Shi-wen, X Stanton, L Kennedy, L Pala, D Chen, Y Howat, S Renzoni, E Carter, D Bou-Gharios, G Stratton, R Pearson, J Beier, F Lyons, K Black, C Abraham, D Leask, A |
| author_sort | Shi-wen, X |
| collection | OXFORD |
| description | CCN2 is induced by transforming growth factor-beta (TGFbeta) in fibroblasts and is overexpressed in connective tissue disease. CCN2 has been proposed to be a downstream mediator of TGFbeta action in fibroblasts; however, the role of CCN2 in regulating this process unclear. By using embryonic fibroblasts isolated from ccn2-/- mice, we showed that CCN2 is required for a subset of responses to TGFbeta. Affymetrix genome-wide expression profiling revealed that 942 transcripts were induced by TGFbeta greater than 2-fold in ccn2+/+ fibroblasts, of which 345 were not induced in ccn2-/- fibroblasts, including pro-adhesive and matrix remodeling genes. Whereas TGFbeta properly induced a generic Smad3-responsive promoter in ccn2-/- fibroblasts, TGFbeta-induced activation of focal adhesion kinase (FAK) and Akt was reduced in ccn2-/- fibroblasts. Emphasizing the importance of FAK and Akt activation in CCN2-dependent transcriptional responses to TGFbeta in fibroblasts, CCN2-dependent transcripts were not induced by TGFbeta in fak-/- fibroblasts and were reduced by wortmannin in wild-type fibroblasts. Akt1 overexpression in ccn2-/- fibroblasts rescued the TGFbeta-induced transcription of CCN2-dependent mRNA. Finally, induction of TGFbeta-induced fibroblast adhesion to fibronectin and type I collagen was significantly diminished in ccn2-/- fibroblasts. Thus in embryonic fibroblasts, CCN2 is a necessary cofactor required for TGFbeta to activate the adhesive FAK/Akt/phosphatidylinositol 3-kinase cascade, FAK/Akt-dependent genes, and adhesion to matrix. |
| first_indexed | 2024-03-07T02:51:49Z |
| format | Journal article |
| id | oxford-uuid:adf0f577-f8c5-4dbe-a287-1c3f9b11d4e1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:51:49Z |
| publishDate | 2006 |
| record_format | dspace |
| spelling | oxford-uuid:adf0f577-f8c5-4dbe-a287-1c3f9b11d4e12022-03-27T03:39:12ZCCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:adf0f577-f8c5-4dbe-a287-1c3f9b11d4e1EnglishSymplectic Elements at Oxford2006Shi-wen, XStanton, LKennedy, LPala, DChen, YHowat, SRenzoni, ECarter, DBou-Gharios, GStratton, RPearson, JBeier, FLyons, KBlack, CAbraham, DLeask, ACCN2 is induced by transforming growth factor-beta (TGFbeta) in fibroblasts and is overexpressed in connective tissue disease. CCN2 has been proposed to be a downstream mediator of TGFbeta action in fibroblasts; however, the role of CCN2 in regulating this process unclear. By using embryonic fibroblasts isolated from ccn2-/- mice, we showed that CCN2 is required for a subset of responses to TGFbeta. Affymetrix genome-wide expression profiling revealed that 942 transcripts were induced by TGFbeta greater than 2-fold in ccn2+/+ fibroblasts, of which 345 were not induced in ccn2-/- fibroblasts, including pro-adhesive and matrix remodeling genes. Whereas TGFbeta properly induced a generic Smad3-responsive promoter in ccn2-/- fibroblasts, TGFbeta-induced activation of focal adhesion kinase (FAK) and Akt was reduced in ccn2-/- fibroblasts. Emphasizing the importance of FAK and Akt activation in CCN2-dependent transcriptional responses to TGFbeta in fibroblasts, CCN2-dependent transcripts were not induced by TGFbeta in fak-/- fibroblasts and were reduced by wortmannin in wild-type fibroblasts. Akt1 overexpression in ccn2-/- fibroblasts rescued the TGFbeta-induced transcription of CCN2-dependent mRNA. Finally, induction of TGFbeta-induced fibroblast adhesion to fibronectin and type I collagen was significantly diminished in ccn2-/- fibroblasts. Thus in embryonic fibroblasts, CCN2 is a necessary cofactor required for TGFbeta to activate the adhesive FAK/Akt/phosphatidylinositol 3-kinase cascade, FAK/Akt-dependent genes, and adhesion to matrix. |
| spellingShingle | Shi-wen, X Stanton, L Kennedy, L Pala, D Chen, Y Howat, S Renzoni, E Carter, D Bou-Gharios, G Stratton, R Pearson, J Beier, F Lyons, K Black, C Abraham, D Leask, A CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts. |
| title | CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts. |
| title_full | CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts. |
| title_fullStr | CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts. |
| title_full_unstemmed | CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts. |
| title_short | CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts. |
| title_sort | ccn2 is necessary for adhesive responses to transforming growth factor beta1 in embryonic fibroblasts |
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