Microtubule Involvement in Translational Regulation of Fibronectin Expression by Light Chain 3 of Microtubule-Associated Protein 1 in Vascular Smooth Muscle Cells

Zhou, Bin; Rabinovitch, Marlene

doi:10.1161/01.res.83.5.481

Cited by 34 publications

(32 citation statements)

References 40 publications

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“…8). Moreover, immunoprecipitation with antiphosphotyrosine antibody followed by Western blotting with the antibody recognizing 15-kDa LC3 microtubule-associated protein 1, showed significant up-regulation of this protein (data not shown), which is also known as a factor facilitating translation of fibronectin mRNA (54). DISCUSSION Results presented in this report showed that, similar to other cell types (15)(16)(17)(18)(19), cultured SMC isolated from porcine coronary FIG.…”

Section: Resultsmentioning

confidence: 58%

Signaling Pathways Transduced through the Elastin Receptor Facilitate Proliferation of Arterial Smooth Muscle Cells

Mochizuki

Brassart

Hinek

2002

Journal of Biological Chemistry

219

148

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In this report we demonstrate that soluble peptides, elastin degradation products stimulate proliferation of arterial smooth muscle cells. We show that these effects are due to generation of intracellular signals transduced through the cell surface elastin receptor, which consists of peripheral 67-kDa elastin-binding protein (EBP) (spliced variant of ␤-galactosidase), immobilized to the transmembrane sialidase and the protective protein. We found that elastin receptor-transduced signaling triggers activation of G proteins, opening of L-type calcium channels, and a sequential activation of tyrosine kinases: FAK, c-Src, platelet-derived growth factorreceptor kinase and then Ras-Raf-MEK1/2-ERK1/2 phosphorylation cascade. This, in turn, causes an increase in expression of cyclins and cyclin-dependent kinases, and a consequent increase in cellular proliferation. The EBP-transduced signals also induce tyrosine kinase-dependent phosphorylation of ␤-tubulin, LC3, microtubule-associated protein 1, and ␣-actin and troponin-T, which could be linked to reorganization of cytoskeleton. We have also disclosed that induction of these signals can be abolished by anti-EBP antibody or by galactosugars, which cause shedding of EBP from the cell surface. Moreover, elastin-derived peptides did not induce proliferation of EBP-deficient cells derived from patients bearing a nonsense mutation of the ␤-galactosidase gene or sialidase-deficient cells from patients with congenital sialidosis.It has been well established that formation of neointima in vascular diseases is associated with impaired assembly of tropoelastin into insoluble elastin (1-6) and with extensive degradation of the elastin-rich extracellular matrix by numerous proteinases leaking from the serum and secreted from the infiltrating platelets, leukocytes, and activated vascular cells (7-10). It has also been suggested that local accumulation of non-assembled tropoelastin and small elastin-derived peptides may constitute an important factor in the activation of the normally quiescent medial SMC 1 into the proliferative and migratory phenotype, which participates in the formation of the occlusive neointima in vascular diseases (2,3,(11)(12)(13)(14)(15) Elastin does not contain the RGD sequence and does not interact with cell surface integrins. Our previous studies demonstrated that numerous cell types, including vascular myocytes, express the cell surface elastin receptor complex, which consists of three subunits (25,26), and that the average cell contains ϳ2 ϫ 10 6 elastin binding sites with the binding affinity (K d ) of 8 nM (27). We found that two of those subunits (55-and 61-kDa) are anchored to the plasma membrane, whereas the third, a peripheral 67-kDa protein, actually binds elastin (25). This major functional component of the receptor complex was named the elastin binding protein (EBP). The repeat hexapeptide in tropoelastin, VGVAPG, has been identified as a chief ligand for high affinity binding to this cell surface receptor (25-27). It has been later established t...

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Section: Resultsmentioning

confidence: 58%

Signaling Pathways Transduced through the Elastin Receptor Facilitate Proliferation of Arterial Smooth Muscle Cells

Mochizuki

Brassart

Hinek

2002

Journal of Biological Chemistry

219

148

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“…This brings forth the interesting possibility that microtubules and/or associated factors coordinate efficient translation of a subset of proteins. Supporting this idea, it has been previously reported that microtubule disruption reduces fibronectin mRNA prevalence in polyribosomes of smooth muscle cells 39 . Given these observations, it is tempting to speculate that microtubules coordinate the organization of polyribosome structures, which may be preferentially associated with a subset of mRNAs.…”

Section: Discussionmentioning

confidence: 70%

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

et al. 2015

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In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.

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“…LC3B acts as a positive regulator of fibronectin (Fn1) mRNA translation, through direct binding to an AU-rich region of the Fn1 39-UTR (44,45). LC3B-dependent fibronectin expression and downstream increases in connective tissue growth factor expression were associated with tumor cell proliferation, adhesion, and invasiveness in fibrosarcoma cells (46).…”

Section: Discussionmentioning

confidence: 99%

Autophagic Protein LC3B Confers Resistance against Hypoxia-induced Pulmonary Hypertension

Lee¹,

Smith²,

Guo³

et al. 2011

Am J Respir Crit Care Med

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194

168

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Rationale: Pulmonary hypertension (PH) is a progressive disease with unclear etiology. The significance of autophagy in PH remains unknown. Objectives: To determine the mechanisms by which autophagic proteins regulate tissue responses during PH. Methods: Lungs from patients with PH, lungs from mice exposed to chronic hypoxia, and human pulmonary vascular cells were examined for autophagy using electron microscopy and Western analysis. Mice deficient in microtubule-associated protein-1 light chain-3B (LC3B 2/2 ), or early growth response-1 (Egr-1 2/2 ), were evaluated for vascular morphology and hemodynamics. Measurements and Main Results: Human PH lungs displayed elevated lipid-conjugated LC3B, and autophagosomes relative to normal lungs. These autophagic markers increased in hypoxic mice, and in human pulmonary vascular cells exposed to hypoxia. Egr-1, which regulates LC3B expression, was elevated in PH, and increased by hypoxia in vivo and in vitro. LC3B 2/2 or Egr-1 2/2 , but not Beclin 1 1/2 , mice displayed exaggerated PH during hypoxia. In vitro, LC3B knockdown increased reactive oxygen species production, hypoxiainducible factor-1a stabilization, and hypoxic cell proliferation. LC3B and Egr-1 localized to caveolae, associated with caveolin-1, and trafficked to the cytosol during hypoxia. Conclusions:The results demonstrate elevated LC3B in the lungs of humans with PH, and of mice with hypoxic PH. The increased susceptibility of LC3B 2/2 and Egr-1 2/2 mice to hypoxia-induced PH and increased hypoxic proliferation of LC3B knockdown cells suggest adaptive functions of these proteins during hypoxic vascular remodeling. The results suggest that autophagic protein LC3B exerts a protective function during the pathogenesis of PH, through the regulation of hypoxic cell proliferation.Keywords: autophagy; hypoxia; hypertension, pulmonary Pulmonary hypertension (PH) is functionally characterized by elevations in mean pulmonary pressure and the development of secondary right ventricular failure. Category I PH, also known as pulmonary arterial hypertension (PAH), includes idiopathic (IPAH), familial, and acquired forms resulting from collagen vascular disease, drugs, HIV infection, portal hypertension, and pulmonary artery shunts (1-5). Categories II-V of PH include those forms secondary to left-heart disease; lung disease or hypoxia; chronic thrombotic or embolic disease; or other diseases rarely associated with PH, such as sarcoid or mediastinitis (1, 2). The molecular and cellular basis for the vascular changes associated with PH remains unclear (6). Impaired production of nitric oxide can result in vasoconstriction and smooth muscle cell proliferation, suggesting a role for endothelial dysfunction in PH (7). In addition, variations in the production, expression, or activity of vascular mediators (i.e., endothelin-1, prostacyclins, voltage-gated K 1 -channels), signaling molecules, and growth factors (e.g., transforming growth factor-b, platelet-derived growth factor [PDGF]) have been implicated in hypoxic remodelin...

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Microtubule Involvement in Translational Regulation of Fibronectin Expression by Light Chain 3 of Microtubule-Associated Protein 1 in Vascular Smooth Muscle Cells

Cited by 34 publications

References 40 publications

Signaling Pathways Transduced through the Elastin Receptor Facilitate Proliferation of Arterial Smooth Muscle Cells

Signaling Pathways Transduced through the Elastin Receptor Facilitate Proliferation of Arterial Smooth Muscle Cells

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

Autophagic Protein LC3B Confers Resistance against Hypoxia-induced Pulmonary Hypertension

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