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J. Biol. Chem., Vol. 277, Issue 8, 6153-6161, February 22, 2002

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Activation of Fibroblast Procollagen 1(I) Transcription by Mechanical Strain Is Transforming Growth Factor--dependent and Involves Increased Binding of CCAAT-binding Factor (CBF/NF-Y) at the Proximal Promoter^*

Gisela E. Lindahl^§, Rachel C. Chambers, Jenny Papakrivopoulou, Sally J. Dawson^¶, Marianne C. Jacobsen, Jill E. Bishop, and Geoffrey J. Laurent

From the  Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, Department of Medicine, Royal Free and University College Medical School, The Rayne Institute, 5 University Street, London WC1E 6JJ and ^¶ Molecular Audiology, Department of Immunology and Molecular Pathology, Windeyer Institute, Royal Free and University College Medical School, 46 Cleveland St., London W1T 4JF, United Kingdom

During normal developmental tissue growth and in a number of diseases of the cardiopulmonary system, adventitial and interstitial fibroblasts are subjected to increased mechanical strain. This leads to fibroblast activation and enhanced collagen synthesis, but the underlying mechanisms involved remain poorly understood. In this study, we have begun to identify and characterize mechanical strain-responsive elements in the rat procollagen 1(I) (COL1A1) gene and show that the activity of COL1A1 promoter constructs, transiently transfected into cardiac fibroblasts, was increased between 2- and 4-fold by continuous cyclic mechanical strain. This was accompanied by a ~3-fold increase in the levels of total active transforming growth factor- (TGF-) released into the medium. Inclusion of a pan-specific TGF- neutralizing antibody inhibited strain-induced COL1A1 promoter activation. Deletion analysis revealed the presence of two potential strain response regions within the proximal promoter, one of which contains an inverted CCAAT-box overlapping a GC-rich element. Both mechanical strain and exogenously added TGF-1 enhanced the binding activity of CCAAT-binding factor, CBF/NF-Y, at this site. Moreover, this element was sufficient to confer strain-responsiveness to an otherwise unresponsive SV40 promoter. In summary, this study demonstrates that strain-induced COL1A1 promoter activation in cardiac fibroblasts is TGF--dependent and involves increased binding of CCAAT-binding factor at the proximal promoter. Furthermore, these findings suggest a novel and potentially important TGF- response element in the rat COL1A1 gene.

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