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Protein Kinases and Cytoskeletal Integrity Modulate the Expression of Fibronectin by Affecting Cyclic Adenosine Monophosphate Response Binding Element^*

^* From the Department of Medicine, Pulmonary and Critical Care Division, Atlanta VA Medical Center and the Emory University School of Medicine, Atlanta, GA.

Correspondence to: Jesse Roman, MD, Associate Professor of Medicine, Emory University School of Medicine, Atlanta VA Medical Center, Pulmonary Room 12C 191, 1670 Clairmont Rd, Decatur, GA 30033

Lung injury is characterized by increased expression of the extracellular matrix fibronectin (FN). Although the exact role FN plays in lung injury is unclear, the changes in tissue architecture caused by its deposition and its ability to affect many cellular functions in vitro suggest that regulation of FN expression is necessary for modulation of inflammation and for tissue repair. This is supported by our data demonstrating that FN can trigger immune cell activation and the expression of specific transcription factors such as activator protein-1, which control the expression of genes encoding for proinflammatory molecules. To gain insight into the factors that regulate FN expression, murine NIH3T3 fibroblasts, transfected with the 1.2-kilobase human FN promoter connected to a luciferase reporter gene, were exposed to several stimuli, and the relative induction of the promoter was measured by luminescence. Transcription of the FN gene, with subsequent production of FN protein, was enhanced by treatment with 10% fetal bovine serum. This stimulatory effect was associated with an induction of the transcription factor cyclic adenosine monophosphate response binding element (CREB) and was inhibited by a competing CREB oligonucleotide. Inhibitors of protein kinase C and mitogen-activated protein kinase pathways blocked the serum-induced FN response. Neither type I collagen, fibrin, nor FN had an effect. Disruption of actin microfilaments inhibited, whereas disruption of microtubular assembly enhanced, the serum-induced FN response. The inhibition of FN gene transcription by drugs capable of affecting cytoskeletal integrity was related to effects on the transcription factor CREB. Overall, the data suggest that regulation of FN expression in fibroblasts in response to serum proteins is dependent on the activation of protein kinase C and members of the mitogen-activated protein kinase pathway and on the state of cytoskeletal integrity.

Footnotes

Abbreviations: CREB = cyclic adenosine monophosphate response element binding protein; FN = fibronectin

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Roman, J. Search for Related Content PubMed Articles by Roman, J.