The Expression of novH in Adrenocortical Cells Is Down-regulated by TGFβ1 through c-Jun in a Smad-independent Manner

Lafont, J.; Laurent, M.; Thibout, Hélène; Lallemand, François; Bouc, Yves Le; Atfi, Azeddine; Martinerie, Cécile

doi:10.1074/jbc.m204405200

Cited by 37 publications

(32 citation statements)

References 81 publications

(87 reference statements)

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“…Previous studies indicate that AP-1 is critical for TGFβ-mediated reduction of CCN3 expression in adrenocortical cells (NCI H295R) (Lafont et al 2002). In addition, steroidogenic factor-1 (SF-1) has been shown to transcriptionally downregulate CCN3 in NCI H295R cells (Doghman et al 2007).…”

Section: Discussionmentioning

confidence: 99%

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A novel role of CCN3 in regulating endothelial inflammation

Lin

Natesan

Shi

et al. 2010

Journal of Cell Communication and Signaling

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The vascular endothelium plays a fundamental role in the health and disease of the cardiovascular system. The molecular mechanisms regulating endothelial homeostasis, however, remain incompletely understood. CCN3, a member of the CCN (Cyr61, Ctgf, Nov) family of cell growth and differentiation regulators, has been shown to play an important role in numerous cell types. The function of CCN3 in endothelial cells has yet to be elucidated. Immunohistochemical analysis of CCN3 expression in mouse tissues revealed robust immunoreactivity in the endothelium of large arteries, small resistance vessels, and veins. We found that CCN3 expression in human umbilical vein endothelial cells (HUVECs) is transcriptionally induced by laminar shear stress (LSS) and HMG CoAreductase inhibitors (statins). Promoter analyses identified the transcription factor Kruppel-like factor 2 (KLF2) as a direct regulator of CCN3 expression. In contrast to LSS, proinflammatory cytokines reduced CCN3 expression. Adenoviral overexpression of CCN3 in HUVEC markedly inhibited the cytokine-mediated induction of vascular adhesion molecule-1 (VCAM-1). Consistent with this observation, CCN3 significantly reduced monocyte adhesion. Conversely, CCN3 knockdown in HUVECs resulted in enhancement of cytokine-induced VCAM-1 expression. Concordant effects were observed on monocyte adhesion. Gain and loss-offunction mechanistic studies demonstrated that CCN3 negatively regulates nuclear factor kappaB (NF-κB) activity by reducing its translocation into the nucleus and subsequent binding to the VCAM-1 promoter, suggesting that CCN3's anti-inflammatory effects occur secondary to inhibition of NF-κB nuclear accumulation. This study identifies CCN3 as a novel regulator of endothelial proinflammatory activation.

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Section: Discussionmentioning

confidence: 99%

“…The CCN3 promoter luciferase construct was kindly provided by Dr. C. Martinerie (France) (Lafont et al 2002), this construct was used as template to clone the proximal 492 base pair CCN3 promoter into pGL3-Basic vector (Promega, Madison, WI). CCN3 promoter deletion constructs were generated by PCR.…”

Section: Transient Transfectionmentioning

confidence: 99%

A novel role of CCN3 in regulating endothelial inflammation

Lin

Natesan

Shi

et al. 2010

Journal of Cell Communication and Signaling

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“…CCN2 induces differentiation of myofibroblasts and increased collagen synthesis in concert with EGF, insulin-like growth factor 2 or insulin (Grotendorst et al, 2004;Gore-Hyer et al, 2003). Moreover, although not mitogenic on its own, CCN3 enhances basic-FGF-induced DNA synthesis and upregulates matrix metalloproteinase (MMP)-1 and PAI-1 expression (Lafont et al, 2005a;Lin, C. et al, 2005). In some studies, however, CCN2 has been shown to possess independent yet modest proliferative activity (~20% above control) (Asano et al, 2005).…”

Section: Ccns As Co-factors For the Ecm Growth Factors And Cytokinesmentioning

confidence: 99%

“…Significantly, CCN3 promotes FGF-and PDGF-mediated proliferation of C2C12 myoblast cells in an integrin-dependent fashion (Lafont et al, 2005a). Through integrins, CCN proteins thus probably modify signaling responses to other proteins and, in principle, CCN molecules could modify a wide range of signal transduction pathways.…”

Section: Ccns As Co-factors For the Ecm Growth Factors And Cytokinesmentioning

confidence: 99%

All in the CCN family: essential matricellular signaling modulators emerge from the bunker

Leask

Abraham

2006

Journal of Cell Science

603

660

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The CCN family is a group of six secreted proteins that specifically associate with the extracellular matrix. Structurally, CCN proteins are modular, containing up to four distinct functional domains. CCN family members are induced by growth factors and cytokines such as TGFβ and endothelin 1 and cellular stress such as hypoxia, and are overexpressed in pathological conditions that affect connective tissues, including scarring, fibrosis and cancer. Although CCN family members were discovered over a decade ago, the precise biological role, mechanism of action and physiological function of these proteins has remained elusive until recently, when several key mechanistic insights into the CCN family emerged. The CCNs have been shown to have key roles as matricellular proteins, serving as adaptor molecules connecting the cell surface and extracellular matrix (ECM). Although they appear not to have specific high-affinity receptors, they signal through integrins and proteoglycans. Furthermore, in addition to having inherent adhesive abilities that modulate focal adhesions and control cell attachment and migration, they execute their functions by modulating the activity of a variety of different growth factors, such as TGFβ. CCN proteins not only regulate crucial biological processes including cell differentiation, proliferation, adhesion, migration, apoptosis, ECM production, chondrogenesis and angiogenesis, but also have more sinister roles promoting conditions such as fibrogenesis.

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“…lated through the Smad-independent pathways (32,33). To evaluate whether the Smad pathway is involved in the down-regulation of Cited2 by TGF-␤, an expression plasmid for Smad7, an inhibitory Smad, was introduced into MDA-MB-231 cells through retrovirus-mediated gene transfer ( Fig.…”

Section: Tgf-␤ Down-regulates Cited2 In Mda-mb-231 Cells-chen Et Almentioning

confidence: 99%

Post-transcriptional Control of Cited2 by Transforming Growth Factor β

Chou

2006

Journal of Biological Chemistry

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Cited2 is a transcription factor without typical DNA binding domains. Cited2 interacts with cAMP-responsive element-binding protein-binding protein (CBP)/p300, TFAP2, Lhx2, and nuclear receptors, such as peroxisome proliferator-activated receptor and estrogen receptor to function as a transcriptional modulator. Overexpression of Cited2 in Rat1 cells leads to tumor formation in nude mice, suggesting that Cited2 is a transforming gene. Through microarray analysis, Cited2 was found to be down-regulated by transforming growth factor ␤1 (TGF-␤) in various cell lines. In this study, we confirmed that both mRNA and protein levels of Cited2 are down-regulated in MDA-MB-231 breast cancer cells. Overexpression of Smad7 or knockdown of Smad4 in MDA-MB-231 cells showed that the Smad pathway is involved in the down-regulation of Cited2. Based on nuclear run-on analysis and Cited2 promoter/reporter assay, Cited2 transcription was not affected by TGF-␤, supporting that down-regulation of Cited2 by TGF-␤ is most likely through post-transcriptional regulation. By using transcriptional inhibitors, we demonstrated that the turnover of Cited2 transcripts appears to be accelerated during TGF-␤ stimulation. Pharmacologic inhibition of translation with cycloheximide attenuated Cited2 down-regulation by TGF-␤. We examined the expression of recombinant Cited2 gene introduced into MDA-MB-231 cells by stable transfection, and we found that mRNA containing the Cited2 protein-coding region controlled by a heterologous promoter indeed responds to TGF-␤-mediated down-regulation. Study from Cited2 deletion mutants showed that the C-terminal conserved region of Cited2 coding sequence is essential for the down-regulation. This is the first demonstration that TGF-␤-mediated down-regulation of Cited2 is post-transcriptional, through the Smad pathway, and requires the presence of its coding sequence. Cited2 (cAMP-responsive element-binding protein-binding protein (CBP)2 /p300-interacting transactivators with glutamic acid and aspartic acid-rich tail) is one of the founding members of transcriptional activators, previously named melanocyte-specific gene-related gene (MRG)1/p35srj (1-4). The members in this family function as transcriptional modulators through interaction with the p300/CBP complex (5-7). Cited2 interacts with Lhx2 to enhance the recruitment of CBP/ p300 and the TATA-binding protein leading to transcription of glycoprotein hormone ␣ subunit genes (5). On the other hand, Cited2 competes with HIF-1␣ for binding to the CH1 domain of p300, and functions as a negative modulator in the hypoxia signaling pathway (2). In addition, Cited2 interacts with TFAP2 (8) and nuclear receptors such as estrogen receptor (9) and peroxisome proliferator-activated receptor (10) to function as a transcriptional coactivator. Cited2 Ϫ/Ϫ mouse embryos die during mid-gestation with profound developmental abnormalities, including cardiac malformations, exencephaly, and adrenal agenesis (11-13). Cited2 acts upstream of Nodal, a member of the TGF-␤ superfamily, an...

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The Expression of novH in Adrenocortical Cells Is Down-regulated by TGFβ1 through c-Jun in a Smad-independent Manner

Cited by 37 publications

References 81 publications

A novel role of CCN3 in regulating endothelial inflammation

A novel role of CCN3 in regulating endothelial inflammation

All in the CCN family: essential matricellular signaling modulators emerge from the bunker

Post-transcriptional Control of Cited2 by Transforming Growth Factor β

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