| Title | Increased cAMP levels modulate transforming growth factor(TGF-{beta})/SMAD-induced expression of extracellular matrix components and other key fibroblast effector functions. | | Author(s) | Schiller M, Dennler S, Anderegg U, Kokot A, Simon JC, Luger TA, Mauviel A, Bohm M | | Institution | Dept. of Dermatology and Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Germany; | | Source | J Biol Chem 2009 Oct 26. | | Abstract | cAMP is a key messenger of a variety of hormones and neuropeptides some of which modulate the composition of extracellular matrix (ECM). Treatment of human dermal fibroblasts with db-cAMP and forskolin strongly antagonized the inductive effects of TGFbeta on the expression of collagen, connective tissue growth factor, tissue inhibitor of matrix metalloproteinase-1 and plasminogen activator inhibitor type I, four prototypical TGFbeta responsive genes. Increased intracellular cAMP prevented TGFbeta-induced SMAD-specific gene transactivation, while TGFbeta-mediated SMAD phosphorylation and nuclear translocation remained unaffected. However, increased cAMP levels abolished entirely TGFbeta-induced interaction of SMAD3 with its transcriptional coactivator CBP/p300. Furthermore, overexpression of the transcriptional coactivator CBP/p300 rescued SMAD-specific gene transcription in the presence of cAMP. These results suggest sequestration of limited amounts of the transcriptional co-activators CBP/p300 by the activated cAMP/CREB pathway as the molecular basis of this inhibitory effect. The relevance of these TGFbeta antagonistic effects of cAMP was extended by two functional in vitro assays. Increased intracellular cAMP levels suppressed the inductive activity of TGFbeta to contract mechanically unloaded collagen lattices and resulted in an attenuation of fibroblast migration of mechanically induced cell layer wounds. Of note, cAMP antagonized by no means all TGFbeta-mediated effects as shown by synergistic effects of increased cAMP levels on hyaluronan synthase 2 (HAS2) expression and hyaluronan secretion, presumably mediated by putative CREB bindings sites adjacent to SMAD binding sites within the HAS2 promoter. Our findings identify the cAMP pathway in fibroblasts as a potent but differential and promoter-specific regulator of various TGFbeta mediated effects involved in ECM homeostasis. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19858184 |
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