α2β1-integrin signaling by itself controls G1/S transition in a human adenocarcinoma cell line (Caco-2): implication of NADPH oxidase-dependent production of ROS

Honoré, Stéphane; Kovacic, Hervé; Pichard, Véronique; Briand, Claudette; Rognoni, J. B.

doi:10.1016/s0014-4827(02)00038-1

Cited by 71 publications

(59 citation statements)

References 47 publications

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“…Nox enzymes both affect ECM synthesis and structure, and mediate the cellular effects of ECM [144]. In colon carcinoma cells, Nox1 controls the expression of specific integrins at the cell surface, and integrindependent attachment/signaling stimulates the G1/S transition [145]. In A431 carcinoma cells, the growth factor EGF activates Nox-dependent ROS generation, and this in turn regulates expression of integrins, cell attachment properties and cell survival [146].…”

Section: F Nox Enzymes and Integrin Signalingmentioning

confidence: 99%

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Lambeth¹

2007

Free Radical Biology and Medicine

581

454

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Section: F Nox Enzymes and Integrin Signalingmentioning

confidence: 99%

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Lambeth¹

2007

Free Radical Biology and Medicine

581

454

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“…Western blot analysis revealed that, unlike mesangial cells lacking integrin a1b1, which produce significantly more collagen IV than WT cells, integrin a2KO mesangial cells produce significantly less collagen ( Figure 5, A and B). Because integrin a2b1 is a positive regulator of profibrotic ROS 11 and integrin a1KO mesangial cells synthesize more collagen IV than WT cells, in part because of increased production of ROS, 3 we examined ROS production by a2KO mesangial cells. As described previously, integrin a1KO cells produce significantly more ROS than WT cells; however, surprisingly, no significant difference in the ROS levels between WT and integrin a2KO cells was found ( Figure 5C).…”

Section: Reduced Collagen IV Production In Mesangial Cells Lacking Inmentioning

confidence: 99%

“…The latter study is more consistent with literature in nonrenal cells indicating that integrin a2b1 is a positive regulator of collagen and ROS synthesis. 10,11 Furthermore, integrin a2b1 expression is required for TGF-b-mediated collagen gel contraction and remodeling, 12 and increased expression of integrin a2b1, both at baseline and after TGF-b treatment, has been detected in fibroblasts derived from patients with hereditary gingival fibromatosis. 13 Thus, despite the development of proteinuria and mild fibrosis in the integrin a2-null mice, the data suggest that, in contrast to integrin a1b1, integrin a2b1 is a positive regulator of collagen synthesis, and its upregulation is associated with fibrotic diseases.…”

mentioning

confidence: 99%

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

Borza

Su²,

Chen³

et al. 2012

Journal of the American Society of Nephrology

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Mesangial cells and podocytes express integrins a1b1 and a2b1, which are the two major collagen receptors that regulate multiple cellular functions, including extracellular matrix homeostasis. Integrin a1b1 protects from glomerular injury by negatively regulating collagen production, but the role of integrin a2b1 in renal injury is unclear. Here, we subjected wild-type and integrin a2-null mice to injury with adriamycin or partial renal ablation. In both of these models, integrin a2-null mice developed significantly less proteinuria and glomerulosclerosis. In addition, selective pharmacological inhibition of integrin a2b1 significantly reduced adriamycin-induced proteinuria, glomerular injury, and collagen deposition in wildtype mice. This inhibitor significantly reduced collagen synthesis in wild-type, but not integrin a2-null, mesangial cells in vitro, demonstrating that its effects are integrin a2b1-dependent. Taken together, these results indicate that integrin a2b1 contributes to glomerular injury by positively regulating collagen synthesis and suggest that its inhibition may be a promising strategy to reduce glomerular injury and proteinuria. The most common cause of end stage kidney disease is glomerulosclerosis, which is characterized by excessive collagen deposition in the glomerulus. Although numerous disease processes can initiate glomerular injury, they all result in abnormal glomerular collagen homeostasis with progression. Glomerular collagen turnover is regulated by multiple factors, including growth factors and profibrotic reactive oxygen species (ROSs) as well as cell extracellular matrix interactions mediated by the matrix receptors integrins (reviewed in ref. 1). Of these factors, the mechanisms by which integrins regulate glomerulosclerosis are the most poorly understood.Integrins consist of two noncovalently associated a-and b-subunits that combine to form 24 different heterodimers in mammals (reviewed in ref.2). The integrin extracellular domains contain the ligand binding site and confer ligand specificity, whereas the cytoplasmic domain interacts with the cytoskeleton and regulates cell signaling. Integrins control critical cell functions, including proliferation, survival, migration, and matrix homeostasis (reviewed in refs. 1 and 2). Thus, it is not surprising that integrins regulate tissue responses to injury in whole organisms.The best-studied integrin in the context of glomerular injury is the major collagen IV receptor, integrin a1b1, which is expressed by mesangial cells 3 and podocytes. 4 We have shown that integrin

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“…Treatment of A431 cells with ␣2␤1 integrin blocking antibodies led to a shift of 3D towards 2D cell populations and these results corroborated previous observations concerning ␣2␤1 integrin-dependant A431 cellular reorganization and survival. 14 Since it was recently shown that ␣2␤1 integrin was also involved in Caco-2 cell growth and that this phenomenon required ROS production, 34 we further analyzed the potential role of the oxidative status of EGF-treated A431 cells in their survival process.…”

Section: A431 Survival Was Correlated To a Balance Between 2d/3d Popumentioning

confidence: 99%

Monolayer versus aggregate balance in survival process for EGF‐induced apoptosis in A431 carcinoma cells: Implication of ROS‐P38 MAPK‐integrin α2β1 pathway

Morazzani

Carvalho

Kovacic

et al. 2004

Intl Journal of Cancer

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A431 cells escape EGF-induced apoptosis by forming cell aggregates. We show that these clusters migrate and merge with neighboring ones, resulting in larger structures composed of a multilayer central (3D) population surrounded by a cell monolayer (2D). We found that after 48 hr of 10 nM EGF treatment, 3D structure formation correlates with ␣2␤1 integrin upregulation. Blockade of ␣2 integrin impairs 3D structure formation. We studied the involvement of reactive oxygen species (ROS) in this process. We show that A431 cells express the NADPH oxidase catalytic subunits Nox1. EGF-induced dose-dependant ROS production was inhibited by the NADPH oxidase inhibitor, diphenylene iodonium (DPI), in these cells while rotenone was ineffective. Inhibition of ROS level in A431 cells with DPI or ebselen (glutathione peroxydase mimic) as well as P38 MAP kinase inhibition by SB203580 decreases ␣2 integrin subunit expression and induces a shift to 3D versus 2D populations. Cell cycle analysis of 2D cells shows that DPI, ebselen and SB203580 decrease the number of cells in S/G2 phase without affecting the cell number in mitosis phase. On the contrary, for 3D cells, these treatments increased the proportion of cells in mitosis without modification of the cell number in S/G2 phase. For both populations, apoptosis was increased by DPI and ebselen. Resistance of cell aggregates by paclitaxel to cell death is usually described. We show that DPI abolishes paclitaxel resistance of 3D cell aggregates. We observed a greater than additive effect between paclitaxel and DPI resulting in an increased proportion of cells in S/G2 phase for 3D populations. These results suggested that the ROS-P38 MAP kinase-␣2␤1 integrin pathway was implicated in the A431 survival process by modulating the balance between 2D/3D cells. © 2004 Wiley-Liss, Inc. Key words: reactive oxygen species; ␣2␤1 integrin; P38 MAP kinase; EGF receptor; adenocarcinoma A431 cell; apoptosis resistance; paclitaxel Epidermal growth factor (EGF) stimulates growth of a great variety of normal and tumoral cells. 1 Nevertheless, a number of tumor cells that overexpress EGF receptors (EGFR) are growthinhibited upon EGF treatment. 2,3 This paradoxical phenomenon has been best characterized in human squamous carcinoma A431 cells, which express a high number of EGFR. 4 These cells have thus been shown to exhibit a biphasic response to EGF in that they are weakly stimulated by picomolar concentrations of EGF but exhibit marked inhibition of proliferation in the presence of nanomolar EGF. 3,5 The growth-inhibitory action of EGF can lead to cell cycle block due to elevation of cyclin-dependent kinase inhibitor p21/CIP1 protein level correlated to G1/S arrest 6 -8 and/or to apoptosis. 9 -11 In A431 cells and in MDA-MB-468, another human cancer cell line overexpressing EGFR, the p21/CIP1-dependent STAT signaling pathway was shown to be required for apoptosis. 12,13 Nevertheless, a proportion of A431 cells escape the EGF-induced apoptosis process and these survival cells were characteriz...

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α2β1-integrin signaling by itself controls G1/S transition in a human adenocarcinoma cell line (Caco-2): implication of NADPH oxidase-dependent production of ROS

Cited by 71 publications

References 47 publications

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

Monolayer versus aggregate balance in survival process for EGF‐induced apoptosis in A431 carcinoma cells: Implication of ROS‐P38 MAPK‐integrin α2β1 pathway

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