RAS and TGF-β exert antagonistic effects on extracellular matrix gene expression and fibroblast transformation

Wisdom, Ron; Huynh, Lyanne; Hsia, Datsun A.; Kim, Sungeun

doi:10.1038/sj.onc.1208870

Cited by 18 publications

(18 citation statements)

References 37 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The similar but independent effects of inhibitors of Rho kinase and Erk on the expression of fibronectin and ␣-SMA in association with decreased actin stress fibers and cell shape changes points out the significance of myosin II-derived contractile force in the regulation of fibronectin and ␣-SMA expression. Our observations regarding the role of Erk activity in the regulation of expression of fibronectin and other ECM molecules in TM cells are consistent with published observations in which TGF-␤ 2 and other cytokines have been shown to stimulate fibronectin expression in an Erk-dependent manner in different cell types (31,44,59). Very recently, ECM rigidity has been reported to increase fibronectin fibril formation, Erk activation, focal adhesion kinase activity, ␣-SMA, and actin stress fibers in TM cells, further reiterating the significance of mechanotransduction in the aqueous humor outflow pathway (45).…”

Section: Discussionsupporting

confidence: 80%

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Pattabiraman¹,

Rao

2010

American Journal of Physiology-Cell Physiology

172

228

View full text Add to dashboard Cite

Pattabiraman PP, Rao PV. Mechanistic basis of Rho GTPaseinduced extracellular matrix synthesis in trabecular meshwork cells. Am J Physiol Cell Physiol 298: C749 -C763, 2010. First published November 25, 2009 doi:10.1152/ajpcell.00317.2009.-Elevated intraocular pressure arising from impaired aqueous humor drainage through the trabecular pathway is a major risk factor for glaucoma. To understand the molecular basis for Rho GTPase-mediated resistance to aqueous humor drainage, we investigated the possible interrelationship between actomyosin contractile properties and extracellular matrix (ECM) synthesis in human trabecular meshwork (TM) cells expressing a constitutively active form of RhoA (RhoAV14). TM cells expressing RhoAV14 exhibited significant increases in fibronectin, tenascin C, laminin, ␣-smooth muscle actin (␣-SMA) levels, and matrix assembly in association with increased actin stress fibers and myosin light-chain phosphorylation. RhoAV14-induced changes in ECM synthesis and actin cytoskeletal reorganization were mimicked by lysophosphatidic acid and TGF-␤2, known to increase resistance to aqueous humor outflow and activate Rho/Rho kinase signaling. RhoAV14, lysophosphatidic acid, and TGF-␤ 2 stimulated significant increases in Erk1/2 phosphorylation, paralleled by profound increases in fibronectin, serum response factor (SRF), and ␣-SMA expression. Treatment of RhoA-activated TM cells with inhibitors of Rho kinase or Erk, on the other hand, decreased fibronectin and ␣-SMA levels. Although suppression of SRF expression (both endogenous and RhoA, TGF-␤ 2-stimulated) via the use of short hairpin RNA decreased ␣-SMA levels, fibronectin was unaffected. Conversely, fibronectin induced ␣-SMA expression in an SRF-dependent manner. Collectively, data on RhoA-induced changes in actomyosin contractile activity, ECM synthesis/assembly, and Erk activation, along with fibronectin-induced ␣-SMA expression in TM cells, reveal a potential molecular interplay between actomyosin cytoskeletal tension and ECM synthesis/assembly. This interaction could be significant for the homeostasis of aqueous humor drainage through the pressure-sensitive trabecular pathway. fibronectin; actomyosin; extracellular signal-regulated kinases; serum response factor GLAUCOMA IS A SECOND MAJOR cause of blindness in the United States. A major risk factor for primary open-angle glaucoma is elevated intraocular pressure caused by increased resistance to aqueous humor outflow localized within the trabecular pathway (15,56). Abnormal accumulation of extracellular matrix (ECM) and/or extracellular material, which increases resistance to drainage of aqueous humor through the trabecular pathway, is believed to be partly responsible for the elevated intraocular pressure and primary open-angle glaucoma (24,28,49). The cellular mechanisms that regulate the production and turnover of ECM within the outflow pathway and how ECM turnover is linked to regulation of aqueous humor outflow through the trabecular meshwork (TM) are far from clearly understood (13,...

show abstract

Section: Discussionsupporting

confidence: 80%

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Pattabiraman¹,

Rao

2010

American Journal of Physiology-Cell Physiology

172

228

View full text Add to dashboard Cite

show abstract

“…We and others have used different approaches to analyze gene expression induced during cell transformation by Fos and Jun proteins (10,19,25,26,35). These data support the idea that part of the transcriptional program induced by transforming Fos and Jun proteins may involve cooperation with Ets proteins.…”

Section: Discussionsupporting

confidence: 60%

Cooperative DNA Binding with AP-1 Proteins Is Required for Transformation by EWS-Ets Fusion Proteins

Kim

Denny

Wisdom

2006

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

“…In yet another study, an antagonistic effect was observed between TGF-␤ and Ras/Raf/ERK signaling (19). These seemingly conflicting observations have added complexity to the mechanism of TGF-␤ action.…”

Section: Tgf-␤ Inhibits Erk Activation In Tcr-activated Naive Cd4mentioning

confidence: 94%

Cutting Edge: TGF-β-Induced Expression of Foxp3 in T cells Is Mediated through Inactivation of ERK

Luo

Zhang²,

Liu³

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

The peripheral induction of T regulatory cells can be accomplished by TGF-β through an epigenetic regulation leading to the expression of Foxp3. However, the exact mechanism of such a TGF-β-mediated action remains unclear. In the current study, we found that TGF-β treatment of CD4+CD25− T cells during T cell activation led to a transient inhibition of the phosphorylation of ERK followed by the induction of Foxp3 expression in these cells. Direct treatment with a specific ERK inhibitor, UO126, during CD4+CD25− T cell activation also induced Foxp3 expression and conferred a suppressive function to the induced Foxp3+ T cells. Furthermore, treatment of T cells with either TGF-β or UO126 significantly down-regulated the expression of DNMTs, a reaction normally elicited by demethylation agents, such as 5-Aza-2′-deoxycytidine. These results indicate that the epigenetic regulation of TGF-β-induced expression of Foxp3 may be mediated through the inactivation of ERK.

show abstract

RAS and TGF-β exert antagonistic effects on extracellular matrix gene expression and fibroblast transformation

Cited by 18 publications

References 37 publications

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Cooperative DNA Binding with AP-1 Proteins Is Required for Transformation by EWS-Ets Fusion Proteins

Cutting Edge: TGF-β-Induced Expression of Foxp3 in T cells Is Mediated through Inactivation of ERK

Contact Info

Product

Resources

About