2014
DOI: 10.1007/s12079-014-0229-7
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ALK5 inhibition blocks TGFβ‐induced CCN1 expression in human foreskin fibroblasts

Abstract: The potent profibrotic cytokine TGFβ induces connective tissue growth factor (CCN2/CTGF) is induced in fibroblasts in a fashion sensitive to SB-431542, a specific pharmacological inhibitor of TGFβ type I receptor (ALK5). In several cell types, TGFβ induces CCN1 but suppresses CCN3, which opposes CCN1/CCN2 activities. However, whether SB-431542 alters TGFβ-induced CCN1 or CCN3 in human foreskin fibroblasts in unclear. Here we show that TGFβ induces CCN1 but suppresses CCN3 expression in human foreskin fibroblas… Show more

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Cited by 9 publications
(9 citation statements)
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References 46 publications
(48 reference statements)
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“…In our initial experiments, as a control, we also treated cells in the presence or absence of ALK5 inhibitor, as ALK5 is the TGFbeta type I receptor for fibroblasts [4]. As expected, TGFbeta1 induced CCN1 and CCN2 mRNA and protein, consistent with prior studies [16, 37] (Fig 1). Moreover, consistent with our prior studies, ALK5 inhibition blocked TGFbeta1 induced CCN1 mRNA and protein in human dermal fibroblasts [38] (Fig 1).…”
Section: Resultssupporting
confidence: 78%
See 1 more Smart Citation
“…In our initial experiments, as a control, we also treated cells in the presence or absence of ALK5 inhibitor, as ALK5 is the TGFbeta type I receptor for fibroblasts [4]. As expected, TGFbeta1 induced CCN1 and CCN2 mRNA and protein, consistent with prior studies [16, 37] (Fig 1). Moreover, consistent with our prior studies, ALK5 inhibition blocked TGFbeta1 induced CCN1 mRNA and protein in human dermal fibroblasts [38] (Fig 1).…”
Section: Resultssupporting
confidence: 78%
“…CCN3 was readily detected NCI-H295R cells, a tumor line that expresses CCN3 [33], indicating the validity of our method of detecting CCN3 protein (Fig 1). That is, CCN3 does not appear to be basally expressed by proliferating human dermal fibroblasts (Previous studies have shown that low levels of intracellular CCN3 are produced in fibroblasts in culture; in growing cells the expression of CCN3 protein is quickly downregulated [37]). Collectively however, these data are consistent with the idea that, at least at the mRNA level, TGFbeta1 has opposing effects on CCN1 and CCN2 as compared to CCN3 in human dermal fibroblasts and that this effect is mediated by ALK5.…”
Section: Resultsmentioning
confidence: 99%
“…The inactivation of either one in the reaction chains will lead to impairment of the TGF-β-mediated cell growth and proliferation. This indicates that down-regulated Tgfbr1 expression or Smad2/3 phosphorylation will block the activation of latent TGF-β [47][48][49]. To further identify whether the TGF-β signaling is affected by the expression of miR-181a-5p in MTEC1 cells, the protein levels of p-Smad2 and p-Smad3 were measured in MTEC1 cells.…”
Section: Discussionmentioning
confidence: 99%
“…Three weeks postnatally, ccn1 f/f mice hemizygous for COL1A2-CRE(ER)T were treated with tamoxifen or corn oil to generate mice deleted or not for CCN1 in fibroblasts (as described in Methods , these mice are subsequently described as CCN1 −/− or CCN1 f/f , respectively). Deletion of CCN1 was verified by genotyping, extraction of dermal fibroblasts for qPCR analysis and subjecting dermal fibroblasts treated with or without TGFβ1, which induces CCN1 protein expression [ 19 ] to Western blot analysis with an anti-CCN1 antibody ( Fig. 1 A–C).…”
Section: Resultsmentioning
confidence: 99%
“…After CCN2, CCN1 (cyr61) is the second most-studied CCN family member. Both CCN1 and CCN2 are induced in fibroblasts by TGFβ1 via ALK5/NOX1/4, and are upregulated in response to mechanotransduction by the Hippo/YAP pathway [ [19] , [20] , [21] , [22] ]. CCN1, like all CCN family members, is composed of an N–terminal signal peptide followed by 4 conserved structural domains, namely: the insulin-like growth factor binding protein (IGFBP) domain, the von Willebrand factor type C (VWC) domain, the thrombospondin type 1 (TSP1) domain, and the C–terminal (CT) heparin-binding domain [ 6 , 7 ].…”
Section: Introductionmentioning
confidence: 99%