Regulation of Transforming Growth Factor-{beta}-dependent Cyclooxygenase-2 Expression in Fibroblasts [Mechanisms Of Signal Transduction] (Journal of Biological Chemistry)

Abnormal transforming growth factor-β (TGF-β) signaling is a critical contributor to the pathogenesis of various human diseases ranging from tissue fibrosis to tumor formation. Excessive TGF-β signaling stimulates fibrotic responses. Recent research has focused in the main on the antiproliferative effects of TGF-β in fibroblasts, and it is presently understood that TGF-β-stimulated cyclooxygenase-2 (COX-2) induction in fibroblasts is essential for antifibroproliferative effects of TGF-β. Both TGF-β and COX-2 have been implicated in tumor growth, invasion, and metastasis, and therefore tumor-associated fibroblasts are a recent topic of interest. Here we report the identification of positive and negative regulatory factors of COX-2 expression induced by TGF-β as determined using proteomic approaches. We show that TGF-β coordinately up-regulates three factors, heterogeneous nuclear ribonucleoprotein A/B (HNRPAB), nucleotide diphosphate kinase A (NDPK A), and nucleotide diphosphate kinase A (NDPK B). Functional pathway analysis showed that HNRPAB augments mRNA and protein levels of COX-2 and subsequent prostaglandin E2 (PGE2) production by suppressing degradation of COX-2 mRNA. In contrast, NDPK A and NDPK B attenuated mRNA and protein levels of COX-2 by affecting TGF-β-Smad2/3/4 signaling at the receptor level. Collectively, we report on a new regulatory pathway of TGF-β in controlling expression of COX-2 in fibroblasts, which advances our understanding of pathophysiological mechanisms of TGF-β.