TAK1 Inhibition Accelerates Cellular Senescence of Retinal Pigment Epithelial Cells

Dvashi, Zeev; Green, Yaron; Pollack, Ayala

doi:10.1167/iovs.14-14349

Cited by 11 publications

(7 citation statements)

References 34 publications

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“…As expected, our results showed that the previously identified TAK1 small-molecule inhibitor 5 Z -7-oxozeaenol [42, 43] markedly prevented inflammation in primary alveolar macrophages and fibrosis in lung fibroblasts isolated from silica-exposed rats, respectively. However, we also noticed that 5 Z -7-oxozeaenol exhibited obvious cytotoxicity in primary lung fibroblasts isolated from healthy rats, as indicated by the MTT assay.…”

Section: Discussionsupporting

confidence: 88%

TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis

Liang

Zhang

et al. 2017

Cell Discov

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Pneumoconiosis, caused by inhalation of mineral dusts, is a major occupational disease worldwide. Currently, there are no effective drugs owing to a lack of potential therapeutic targets during either the inflammation or fibrosis molecular events in pneumoconiosis. Here, we performed microarrays to identify aberrantly expressed genes in the above molecular events in vitro and found a hub gene transforming growth factor-β-activated kinase 1 (TAK1), which was highly expressed and activated in pneumoconiosis patients as well as silica-exposed rats with experimental pneumoconiosis. Genetic modulation of TAK1 by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9, RNA interference and overexpression indicated the important role of TAK1 in both inflammation and fibrosis in experimental pneumoconiosis. To achieve pharmacological TAK1 inhibition, we virtually screened out a natural product resveratrol, which targeted TAK1 at both N161 and A107 residues, and significantly inhibited TAK1 activation to attenuate inflammation and fibrosis in vitro. Consistently, in vivo prevention and intervention studies showed that resveratrol could inhibit pulmonary inflammation and fibrosis in silica-exposed rats.

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Section: Discussionsupporting

confidence: 88%

TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis

Liang

Zhang

et al. 2017

Cell Discov

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“…Evidence has indicated that viability of RPE cells is associated with various ophthalmic diseases through regulation of EMT molecular markers ( 22 ). Research has also demonstrated that RPE cell apoptosis is influenced by a combination of macrophages and soluble mediators in the progression of AMD ( 11 ). Additionally, our previous study suggested that TAK1 inhibitor could suppress proliferation and EMT in RPE cells ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, research has indicated that TAK1 is involved in the autophagy process in RPE cells, suggesting that aberrant activity of this kinase impairs autophagy and subsequently leads to alterations in the vitality of RPE cells ( 10 ). In addition, a study by Dvashi et al ( 11 ) demonstrated that inhibition of TAK1 expression accelerated cellular senescence of RPE cells, which elucidated its role in mechanisms underlying RPE cellular senescence induction in the development of dry AMD. Notably, a previous report demonstrated the suppressive effect of LYTAK1 on the proliferation of RPE cells ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

LYTAK1 attenuates proliferation of retinal pigment epithelial cells through TGF‑β‑mediated epithelial‑mesenchymal transition via the ERK/AKT signaling pathway

Chen

Yan

et al. 2017

Exp Ther Med

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Retinal pigment epithelial (RPE) cells have crucial roles in the initiation and development of human ophthalmic diseases. Our previous study suggested that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a potential target in the progression and pathogenesis of human proliferative vitreoretinopathy disease. The present study further analyzed the role of TAK1 inhibitor, LYTAK1, in human RPE cells and explored the potential molecular mechanism of LYTAK1-mediated proliferation of human RPE cells. Proliferation of human RPE cells was investigated following treatment with LYTAK1 and knockdown of TGF-β. TGF-β-mediated epithelial-mesenchymal transition (EMT) through regulation of the extracellular signal-regulated kinase (ERK)/protein kinase B (AKT) signaling pathway was also explored to analyze the LYTAK1-mediated mechanism of proliferation in human RPE cells. The present results demonstrated that LYTAK1 administration suppressed TAK1 gene and protein expression in human RPE cells. LYTAK1 administration also inhibited proliferation and migration of human RPE cells in vitro. Outcomes indicated that LYTAK1 treatment downregulated expression levels of TGF-β1 and EMT markers, including cadherin, fibronectin and α-smooth muscle actin in human RPE cells. Notably, results demonstrated that the ERK/AKT signal pathway was blocked by LYTAK1 in human RPE cells. Knockdown of TGF-β markedly inhibited phosphorylation and activity of TAK1 and suppressed the LYTAK1-mediated ERK/AKT signaling pathway in RPE cells, which further canceled inhibition of RPE cell proliferation by LYTAK1. In conclusion, these findings indicated that LYTAK1 may inhibit RPE cell proliferation through the TGF-β-mediated EMT/ERK/AKT signaling pathway, suggesting that TAK1 may be a potential target for the treatment of RPE diseases.

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“…( 42 , 43 )]. Transforming growth factor β activated kinase 1 (TAK1), a key player in the regulation of autophagy, maintains the normal function of RPE cells ( 44 , 45 ). Recently, it was discovered that autophagy is triggered, when pathogens are bound to CD46 ( 46 ).…”

Section: Hypothesismentioning

confidence: 99%

“…HHV-6 infection can also impair Toll-like receptor signaling by reducing TAK1 activity as shown in infected dendritic cells ( 56 ). When RPE cells are infected with HHV-6A, the essential role of TAK1 for maintaining normal function of RPE cells through regulation of autophagy would be impaired ( 44 , 45 ).…”

Section: Hypothesismentioning

confidence: 99%

Age-Related Macular Degeneration: A Connection between Human Herpes Virus-6A-Induced CD46 Downregulation and Complement Activation?

Fierz

2017

Front. Immunol.

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Viruses are able to interfere with the immune system by docking to receptors on host cells that are important for proper functioning of the immune system. A well-known example is the human immunodeficiency virus that uses CD4 cell surface molecules to enter host lymphocytes and thereby deleteriously destroying the helper cell population of the immune system. A more complicated mechanism is seen in multiple sclerosis (MS) where human herpes virus-6A (HHV-6A) infects astrocytes by docking to the CD46 surface receptor. Such HHV-6A infection in the brain of MS patients has recently been postulated to enable Epstein–Barr virus (EBV) to transform latently infected B-lymphocytes in brain lesions leading to the well-known phenomenon of oligoclonal immunoglobulin production that is widely used in the diagnosis of MS. The cellular immune response to HHV-6A and EBV is one part of the pathogenic mechanisms in MS. A more subtle pathogenic mechanism can be seen in the downregulation of CD46 on astrocytes by the infecting HHV-6A. Since CD46 is central in regulating the complement system, a lack of CD46 can lead to hyperactivation of the complement system. In fact, activation of the complement system in brain lesions is a well-known pathogenic mechanism in MS. In this review, it is postulated that a similar mechanism is central in the development of age-related macular degeneration (AMD). One of the earliest changes in the retina of AMD patients is the loss of CD46 expression in the retinal pigment epithelial (RPE) cells in the course of geographic atrophy. Furthermore, CD46 deficient mice spontaneously develop dry-type AMD-like changes in their retina. It is also well known that certain genetic polymorphisms in the complement-inhibiting pathways correlate with higher risks of AMD development. The tenet is that HHV-6A infection of the retina leads to downregulation of CD46 and consequently to hyperactivation of the complement system in the eyes of susceptible individuals.

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TAK1 Inhibition Accelerates Cellular Senescence of Retinal Pigment Epithelial Cells

Cited by 11 publications

References 34 publications

TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis

TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis

LYTAK1 attenuates proliferation of retinal pigment epithelial cells through TGF‑β‑mediated epithelial‑mesenchymal transition via the ERK/AKT signaling pathway

Age-Related Macular Degeneration: A Connection between Human Herpes Virus-6A-Induced CD46 Downregulation and Complement Activation?

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