TGFβ and CCN2/CTGF mediate actin related gene expression by differential E2F1/CREB activation

Faherty, Noel; O'Donovan, Helen; Kavanagh, David; Madden, Stephen F.; McKay, Gareth J.; Maxwell, Alexander P.; Martin, Finian; Godson, Catherine; Crean, John

doi:10.1186/1471-2164-14-525

Cited by 16 publications

(12 citation statements)

References 41 publications

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“…These highly regulated changes are mediated by GAPs and GEFs such as p190RhoGAP, and ultimately function to facilitate alterations in keratinocyte polarity and motility in response to external stimuli. This mechanism is similar to others regarding CCN2‐induced cell migration in cell types such as osteoblasts, chondrocytes and renal mesangial cells, but is novel in the keratinocyte .…”

Section: Discussionsupporting

confidence: 86%

Cdc42 and p190RhoGAP activation by CCN2 regulates cell spreading and polarity and induces actin disassembly in migrating keratinocytes

Kiwanuka

Lee

Hackl

et al. 2014

International Wound Journal

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Cell migration requires spatiotemporal integration of signals that regulate cytoskeletal dynamics. In response to a migration-promoting agent, cells begin to polarise and extend protrusions in the direction of migration. These cytoskeletal rearrangements are orchestrated by a variety of proteins, including focal adhesion kinase (FAK) and the Rho family of GTPases. CCN2, also known as connective tissue growth factor, has emerged as a regulator of cell migration but the mechanism by which CCN2 regulates keratinocyte function is not well understood. In this article, we sought to elucidate the basic mechanism of CCN2-induced cell migration in human keratinocytes. Immunohistochemical staining was used to demonstrate that treatment with CCN2 induces a migratory phenotype through actin disassembly, spreading of lamellipodia and re-orientation of the Golgi. In vitro assays were used to show that CCN2-induced cell migration is dependent on FAK, RhoA and Cdc42, but independent of Rac1. CCN2-treated keratinocytes displayed increased Cdc42 activity and decreased RhoA activity up to 12 hours post-treatment, with upregulation of p190RhoGAP. An improved understanding of how CCN2 regulates cell migration may establish the foundation for future therapeutics in fibrotic and neoplastic diseases.

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Section: Discussionsupporting

confidence: 86%

Cdc42 and p190RhoGAP activation by CCN2 regulates cell spreading and polarity and induces actin disassembly in migrating keratinocytes

Kiwanuka

Lee

Hackl

et al. 2014

International Wound Journal

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“…JunB, a TGFβ-responsive member of the AP-1 transcription factor family (17), is also upregulated in DCM hearts (2.4-fold, P = 1 × 10 −26 ). Also differentially expressed is E2F transcription factor 1 ( E2f1 , 2.9-fold, P = 3 × 10 −5 ), which is known to play a role in the cardiac stress response (18) and is an important downstream effector of TGFβ in cancer and various fibrotic diseases (19, 20). The cyclic-AMP dependent transcription factor Atf3 (7.4-fold, P = 2 × 10 −44 ), which promotes maladaptive cardiac remodeling and regulates cardiac fibrosis, was also upregulated in PLN R9C/+ (21, 22).…”

Section: Resultsmentioning

confidence: 99%

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

et al. 2016

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Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10−4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10−33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.

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“…Renal interstitial fibrosis and glomerular sclerosis are characteristic hallmarks of DN and several studies have implicated members of the WNT/ β -catenin pathways in these disease processes [ 6 – 9 ]. The WNT pathways can be separated into canonical β -catenin dependent and noncanonical β -catenin independent pathways ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we have assessed common genetic variants within key WNT pathway genes for association with DN [ 22 , 23 ] and there is evidence that many WNT pathway genes are differentially regulated in the pathogenesis of DN [ 6 – 9 ]. In this study we sought to identify cis -acting regulatory elements in groups of coregulated genes by searching for an overrepresentation of known TF binding motifs within the promoters of WNT pathway genes and compare these to a background set of sequences, typically other gene promoters within the genome [ 24 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic Evaluation of Transcriptional Regulation of WNT Pathway Genes with reference to Diabetic Nephropathy

McKay

Kavanagh

Crean

et al. 2016

Journal of Diabetes Research

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Objective. WNT/β-catenin pathway members have been implicated in interstitial fibrosis and glomerular sclerosis disease processes characteristic of diabetic nephropathy (DN), processes partly controlled by transcription factors (TFs) that bind to gene promoter regions attenuating regulation. We sought to identify predicted cis-acting transcription factor binding sites (TFBSs) overrepresented within WNT pathway members. Methods. We assessed 62 TFBS motif frequencies from the JASPAR databases in 65 WNT pathway genes. P values were estimated on the hypergeometric distribution for each TF. Gene expression profiles of enriched motifs were examined in DN-related datasets to assess clinical significance. Results. Transcription factor AP-2 alpha (TFAP2A), myeloid zinc finger 1 (MZF1), and specificity protein 1 (SP1) were significantly enriched within WNT pathway genes (P values < 6.83 × 10−29, 1.34 × 10−11, and 3.01 × 10−6, resp.). MZF1 expression was significantly increased in DN in a whole kidney dataset (fold change = 1.16; 16% increase; P = 0.03). TFAP2A expression was decreased in an independent dataset (fold change = −1.02; P = 0.03). No differential expression of SP1 was detected. Conclusions. Three TFBS profiles are significantly enriched within WNT pathway genes highlighting the potential of in silico analyses for identification of pathway regulators. Modification of TF binding may possibly limit DN progression, offering potential therapeutic benefit.

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TGFβ and CCN2/CTGF mediate actin related gene expression by differential E2F1/CREB activation

Cited by 16 publications

References 41 publications

Cdc42 and p190RhoGAP activation by CCN2 regulates cell spreading and polarity and induces actin disassembly in migrating keratinocytes

Cdc42 and p190RhoGAP activation by CCN2 regulates cell spreading and polarity and induces actin disassembly in migrating keratinocytes

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

Bioinformatic Evaluation of Transcriptional Regulation of WNT Pathway Genes with reference to Diabetic Nephropathy

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