Mice Lacking Smad3 Are Protected Against Cutaneous Injury Induced by Ionizing Radiation

Flanders, Kathleen C.; Sullivan, Catherine D.; Fujii, Makiko; Sowers, Anastasia L.; Anzano, Mario A.; Arabshahi, Alidad; Major, Christopher; Deng, Chu‐Xia; Russo, Angelo; Mitchell, James B.; Roberts, Anita B.

doi:10.1016/s0002-9440(10)64926-7

Cited by 265 publications

(256 citation statements)

References 64 publications

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“…64 Exposure of these mice to radiation-induced injury causes significantly less epidermal acanthosis and dermal influx of mast cells, macrophages, and neutrophils than wild type littermates, demonstrating that these mice have a significantly reduced fibrotic response. 65 Smad4 mice present with inflammatory polyps in the glandular stomach and duodenum consistent with previous reports that Smad4 mutations are involved in a subset of familial juvenile polyposis. 66…”

Section: Tgf-β Knockout Micesupporting

confidence: 92%

Medical Applications of Transforming Growth Factor-

Flanders¹,

Burmester²

2003

Clinical Medicine & Research

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Transforming growth factor-β (TGF-β) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-βs useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-β has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-β have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-β activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.

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Section: Tgf-β Knockout Micesupporting

confidence: 92%

Medical Applications of Transforming Growth Factor-

Flanders¹,

Burmester²

2003

Clinical Medicine & Research

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“…15 The downstream signaling effects of TGF-b are mediated by Smad3. 16 The Smad3 loss can afford protection from radiation-induced fibrosis, 17 bleomycin-induced pulmonary fibrosis, 18 presumably by interrupting the pathways leading up to matrix production by fibroblasts that lead to tubulointerstitial fibrosis. Recent reports indicate that Smad7 is selectively decreased, whereas phosphorylation of Smad2 and Smad3 is increased in UUO model.…”

Section: Discussionmentioning

confidence: 99%

Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-β/Smad activity

Zhang

Sun

Xian

et al. 2010

Laboratory Investigation

108

100

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Transforming growth factor-b (TGF-b) has a pivotal function in the progression of renal fibrosis in a wide variety of renal diseases. Smad proteins have been identified to have an important function in regulating the expression of extracellular matrix (ECM) proteins through TGF-b signaling pathway. Aberrant TGF-b/Smad signaling can be modulated by stabilization of microtubules with paclitaxel. In this study, we investigated if paclitaxel can attenuate tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction (UUO). Rats in groups of six were subjected to UUO and received low-dose intraperitoneal injection of paclitaxel (0.3 mg/kg) twice a week. They were killed at day 7 and 14 after UUO or Sham operation. TGF-b signaling cascade and status of various ECM proteins were evaluated by RT-PCR, western blotting and immunohistochemical or immunofluorescence staining. The paclitaxel treatment markedly suppressed Smad2 and Smad3 phosphorylation. This was associated with attenuated expression of integrin-linked kinase, collagens I and III, fibronectin (FN) and a-smooth muscle actin, and a substantial decrease in renal fibrosis in animals that underwent UUO and received paclitaxel. These data indicate that the low-dose paclitaxel ameliorates renal tubulointerstitial fibrosis by modulating TGF-b signaling, and thus, the paclitaxel may have some therapeutic value in humans.

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“…9 -11), whereas Smad3-mediated TGF␤ signaling is a major culprit in suppressing Prdx6 expression in this scenario. It has been reported that mice lacking Smad3 show accelerated healing (15,89) and has been suggested that Smad3 plays a crucial role in tissue repair during injury (90). Importantly, recently, several reports have come forward documenting the role of PRDX6 in wound healing and in maintaining cell/tissue integrity (24).…”

Section: Discussionmentioning

confidence: 99%

Loss of NF-κB Control and Repression of Prdx6 Gene Transcription by Reactive Oxygen Species-driven SMAD3-mediated Transforming Growth Factor β Signaling

Fatma

Kubo

Takamura

et al. 2009

Journal of Biological Chemistry

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Activation of transforming growth factor ␤ (TGF␤) in response to increased reactive oxygen species (ROS) leads to pathophysiology of cells/tissues by overmodulation of gene transcription. PRDX6 plays a rheostat role in regulating gene transcription by controlling cellular ROS in maintaining homeostasis; thus, fine tuning of Prdx6 expression is required to optimize ROS levels. Ϫ/Ϫ or Prdx6 Ϫ/Ϫ cells was moderately increased by disruption of NF-B sites, suggesting the role of NF-B in tuning of Prdx6 expression. Findings revealed a mechanism of repression and regulation of PRDX6 expression in cells facing stress or aging and provided clues for antioxidant(s)-based new approaches in preventing ROS-driven deleterious signaling. PRDX6 (peroxiredoxin 6) is a member of an emerging peroxiredoxin family that has GSH peroxidase as well as acidic Ca 2ϩ -independent phospholipase A2 activities (1-7). The peroxiredoxins function in concert to detoxify reactive oxygen species (ROS) 2 and play a cytoprotective role by removing ROS and by limiting ROS levels regulating cell survival signaling (1, 3, 4, 6, 8, 9 -11). The unique ability to regulate signaling and to maintain phospholipid turnover distinguishes PRDX6 from the other five peroxiredoxins (PRDX1 to -5). This molecule is widely expressed, occurring in high levels in the liver, lung, eye lens, and keratinocytes (1, 2, 10, 12-18), whereas reduced expression of PRDX6 can lead to cell death and tissue degeneration (10, 11, 15, 19 -22). PRDX6 has been implicated in maintenance of blood vessel integrity in wounded skin (23, 24) and in development and progression of several diseases, including oxidative-induced cataractogenesis (25), psoriasis (12, 26) atherosclerosis (22), and Parkinsonian dementia (27). Accumulating evidence indicates that expression levels of PRDX6 contribute to pathophysiology of cells and tissues. Several studies have reported decreases in antioxidant levels and increases in ROS levels, leading to a decline in a number of physiological functions because of overmodulation of ROS-mediated gene expression and activation of such factors as TGF␤ and NF-B, hallmarks of the aging process and age-associated degenerative diseases (28 -30). However, given the role of ROS as a mediator of normal or redox signaling, we believe that optimal regulation of Prdx6 expression may require fine tuning to avoid overshooting the desired beneficial effects to the point of perturbing the delicate redox balance essential to maintenance of normal cellular function. Recently, using targeted inactivation of the Prdx6 gene, we reported activation and expression of TGF␤ and TGF␤-mediated suppression of Prdx6 mRNA and protein (1,4,5,31), suggesting that this molecule may have a role in repression of Prdx6 transcription. Quantification by staining with H2DCF-DA established a higher prevalence of ROS in these cells. Also, the activation of TGF␤ in Prdx6-deficient cells was associated with ROS and inhibited by PRDX6 overexpression or MnTBAP, a superoxide dismutase mimetic and a known ROS...

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Mice Lacking Smad3 Are Protected Against Cutaneous Injury Induced by Ionizing Radiation

Cited by 265 publications

References 64 publications

Medical Applications of Transforming Growth Factor-

Medical Applications of Transforming Growth Factor-

Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-β/Smad activity

Loss of NF-κB Control and Repression of Prdx6 Gene Transcription by Reactive Oxygen Species-driven SMAD3-mediated Transforming Growth Factor β Signaling

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