Hic-5 Regulates Actin Cytoskeletal Reorganization and Expression of Fibrogenic Markers and Myocilin in Trabecular Meshwork Cells

Pattabiraman, Padmanabhan P; Rao, Ponugoti Vasantha

doi:10.1167/iovs.15-17204

Cited by 17 publications

(21 citation statements)

References 64 publications

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“…S3). Indeed, others have now shown a requirement for Hic-5 in the TGF-β-dependent induction of α-SMA in glomerular mesangial cells, suggesting that this relationship could be conserved in other cell types (Pattabiraman and Rao, 2015).…”

Section: Discussionmentioning

confidence: 96%

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-β on myofibroblast differentiation remains a crucial area of investigation. We report here that the focal adhesion protein, Hic-5 (also known as TGFB1I1), is required for the mechanically dependent generation of stress fibers in response to TGF-β. Successful generation of stress fibers promotes the nuclear localization of the transcriptional co-factor MRTF-A (also known as MKL1), and this correlates with the mechanically dependent induction of α smooth muscle actin (α-SMA) and Hic-5 in response to TGF-β. As a consequence of regulating stress fiber assembly, Hic-5 is required for the nuclear accumulation of MRTF-A and the induction of α-SMA as well as cellular contractility, suggesting a crucial role for Hic-5 in myofibroblast differentiation. Indeed, the expression of Hic-5 was transient in acute wounds and persistent in pathogenic scars, and Hic-5 colocalized with α-SMA expression in vivo. Taken together, these data suggest that a mechanically dependent feed-forward loop, elaborated by the reciprocal regulation of MRTF-A localization by Hic-5 and Hic-5 expression by MRTF-A, plays a crucial role in myofibroblast differentiation in response to TGF-β.

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Section: Discussionmentioning

confidence: 96%

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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“…One such transient adhesome protein is Hic-5 (also called TGFB1I1) whose expression was recently identified to be upregulated by dexamethasome and TGFβ2 in TM cells (Clark et al, 2013; Pattabiraman and Rao, 2015). Hic-5 is an adaptor protein that divides its time between focal adhesions and the nucleus (Thomas et al,1999; Yang et al, 2000; Chodankar et al, 2014).…”

Section: Integrin Adhesomes and Glaucomamentioning

confidence: 99%

“…In TM cells, it co-localized with αvβ3 integrins in focal adhesions and induced stress fiber formation and RhoA activity. Knockdown of its expression suppressed the dexamethasone-induced expression of myocilin, a protein known to be involved in POAG and TGFβ2-induced fibrogenic activity (Pattabiraman and Rao, 2015). Hic-5 shares homology with another adhesome protein called paxillin whose knockdown was also shown to block TGF-β2 responses in TM cells (Takahashi et al, 2013).…”

Section: Integrin Adhesomes and Glaucomamentioning

confidence: 99%

“…Thus, it is interesting that so many changes in the integrin adhesome are detected following TGFβ2 and dexamethasone treatment, since both these treatments are associated with the development of glaucoma. These alterations suggest that these integrin-mediated signaling complexes may be altered in glaucoma and/or could be responsible, in part, for the generation of the glaucomatous phenotype as studies with Hic-5 imply (Pattabiraman and Rao, 2015). …”

Section: Integrin Adhesomes and Glaucomamentioning

confidence: 99%

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The role of integrins in glaucoma

Filla

Faralli

Peotter

et al. 2017

Experimental Eye Research

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Integrins are a family of heterodimeric transmembrane receptors that mediate adhesion to the extracellular matrix (ECM). In addition to their role as adhesion receptors, integrins can act as “bidirectional signal transducers” that coordinate a large number of cellular activities in response to the extracellular environment and intracellular signaling events. This bidirectional signaling helps maintain tissue homeostasis. Dysregulated bidirectional signaling, however, could trigger the propagation of feedback loops that can lead to the establishment of a disease state such as glaucoma. Here we discuss the role of integrins and bidirectional signaling as they relate to the glaucomatous phenotype with special emphasis on the αvβ3 integrin. We present evidence that this particular integrin may have a significant impact on the pathogenesis of glaucoma.

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“…Previous studies have documented that trabecular meshwork endothelial cells may directly alter the composition of the extracellular matrix during oxidative stress, resulting in elevated intraocular pressure (IOP) and glaucoma (20)(21)(22)(23)(24). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a central regulator of cellular oxidation reactions and serves a key role in cell defense mechanisms against oxidative stress (25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork

Cheng¹,

Liang²,

Qi³

2017

Experimental and Therapeutic Medicine

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Abstract. Glaucoma is a major cause of irreversible blindness. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of numerous antioxidants within cells and is therefore a focus of current ophthalmic research. To determine the roles of Nrf2 in mediating the glaucoma trabecular meshwork (GTM), the present study evaluated the levels of Nrf2 expression in GTM and human trabecular meshwork (HTM) cells by reverse-transcription-quantitative polymerase chain reaction and western blot analysis. It was principally observed that Nrf2 expression was downregulated in GTM cells. In addition, to determine the influence of Nrf2 on the apoptosis and proliferation of GTM and HTM cells, transfection assays and western blotting were performed to evaluate the expression of apoptosis-related proteins. The results of the current study indicated that Nrf2 may promote viability and reduce apoptosis in GTM and HTM cells. Collectively, these data suggest that Nrf2 may be a novel therapeutic target to treat glaucoma.

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Hic-5 Regulates Actin Cytoskeletal Reorganization and Expression of Fibrogenic Markers and Myocilin in Trabecular Meshwork Cells

Cited by 17 publications

References 64 publications

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

The role of integrins in glaucoma

Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork

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