Up-regulation of the KLF2 Transcription Factor by Fluid Shear Stress Requires Nucleolin

Huddleson, Justin P.; Ahmad, Nisar; Lingrel, Jerry B.

doi:10.1074/jbc.m513406200

Cited by 51 publications

(33 citation statements)

References 57 publications

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“…28 Nucleolin has also been shown to be necessary for increased expression of Kruppel-like factor 2 in response to shear stress. 29 We have confirmed EC expression of nucleolin in human and murine tissues, with a staining pattern consistent with surface localization. Likewise, calreticulin, despite the lack of a classic secretion peptide or transmembrane domain, is present in human plasma, extracellular matrix, and body fluids, and may be found at increased concentrations in inflammatory disorders such as rheumatoid arthritis.…”

Section: Discussionsupporting

confidence: 58%

“…Given the known roles of calreticulin and nucleolin in EC function and signaling, [27][28][29][30][31] we further examined interactions among annexin A2, TLR4, calreticulin, and nucleolin using immunoprecipitation. Cell extracts prepared from unstimulated ECs or cells incubated with ␤ 2 GPI and anti-␤ 2 GPI Abs were subjected to immunoprecipitation using Abs against annexin A2, TLR4, or nucleolin.…”

Section: Annexin A2 Associates With Other Ec-surface Proteinsmentioning

confidence: 99%

“…[27][28][29][30][31] To examine whether these proteins occur on the surface of ECs in vivo, we stained tissues for nucleolin and calreticulin. We observed robust staining for nucleolin in vascular endothelium in human tonsil and were incubated with ␤2GPI and anti-␤2GPI Abs or TNF␣ to induce activation.…”

Section: Expression Of Nucleolin and Calreticulin On The Cell Surfacementioning

confidence: 99%

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A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

Allen

Fonseca

Betapudi

et al. 2012

Blood

127

114

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Antiphospholipid Abs (APLAs) are associated with thrombosis and recurrent fetal loss. These Abs are primarily directed against phospholipid-binding proteins, particularly ␤ 2 GPI, and activate endothelial cells (ECs) in a ␤ 2 GPI-dependent manner after binding of ␤ 2 GPI to EC annexin A2. Because annexin A2 is not a transmembrane protein, the mechanisms of APLA/anti-␤ 2 GPI Ab-mediated EC activation are uncertain, although a role for a TLR4/myeloid differentiation factor 88-dependent pathway leading to activation of NF-B has been proposed. In the present study, we confirm a critical role for TLR4 in anti-␤ 2 GPI Ab-mediated EC activation and demonstrate that signaling through TLR4 is mediated through the assembly of a multiprotein signaling complex on the EC surface that includes annexin A2, TLR4, calreticulin, and nucleolin. An essential role for each of these proteins in cell activation is suggested by the fact that inhibiting the expression of each using specific siRNAs blocked EC activation mediated by APLAs/anti-␤ 2 GPI Abs. These results provide new evidence for novel proteinprotein interactions on ECs that may contribute to EC activation and the pathogenesis of APLA/anti-␤ 2 GPI-associated thrombosis and suggest potential new targets for therapeutic intervention in antiphospholipid syndrome. (Blood. 2012; 119(3):884-893) IntroductionAntiphospholipid syndrome (APS) is characterized by thrombosis and recurrent fetal loss in patients with circulating antiphospholipid Abs (APLAs) and is the most important cause of acquired thrombophilia. [1][2][3] Prospective studies have demonstrated that patients with APS experience significant morbidity and mortality despite recommendations for indefinite anticoagulation. 4 The term "antiphospholipid" is actually a misnomer, because the majority of APLAs are directed against phospholipid-binding proteins, of which ␤ 2 -glycoprotein I (␤ 2 GPI) is the most common. 5,6 The clinical importance of anti-␤ 2 GPI Abs has been demonstrated in several previous reports, 7 and recent studies have shown that affinity-purified human anti-␤ 2 GPI Abs induce thrombosis in mice. 8 Despite the clinical importance of APS, however, its pathogenesis has not been well defined. 1,3,9 One mechanism by which APLAs/anti-␤ 2 GPI Abs may promote thrombosis is through ␤ 2 GPI-dependent activation of endothelial cells (ECs). [10][11][12] ECs play a critical role in the maintenance of blood fluidity through expression of anticoagulant proteins on their luminal surface and the elaboration of antithrombotic substances. 13 However, EC activation leads to loss of these anticoagulant properties and transformation to a pro-adhesive, procoagulant phenotype. 13 APLAs/anti-␤ 2 GPI Abs induce EC activation in vitro and in vivo, as determined by their ability to increase the expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1), and tissue factor (TF) and to enhance the expression, synthesis, and/or secretion of pro-inflammatory cytokines and chemokines. 3,[10][11][12] These effects may account for the ab...

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Section: Discussionsupporting

confidence: 58%

Section: Annexin A2 Associates With Other Ec-surface Proteinsmentioning

confidence: 99%

Section: Expression Of Nucleolin and Calreticulin On The Cell Surfacementioning

confidence: 99%

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A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

Allen

Fonseca

Betapudi

et al. 2012

Blood

127

114

View full text Add to dashboard Cite

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“…However, our present study showed that the reduction of MK mRNA level because of the suppression of nucleolin transcription by the application of nucleolin antisense probe was about 50%. This phenomenon seems to be caused by following several reasons as follows: 1) transcriptional reduction of nucleolin was not complete even by the antisense probe application, probably because the nucleolin was a ubiquitously expressed gene in cells; 2) it is unknown whether the transcriptional regulation of MK by nucleolin is direct or indirect, and there may be another transcriptional pathway for the MK expression besides nucleolin (39,40); 3) translational disturbance of nucleolin induced by adding antisense probe may influence the stabilization of MK mRNA as shown in previous reports (41,42). It therefore seems important to disclose the molecular interaction between nucleolin and MK in the cellular biology of tooth germ development.…”

Section: Discussionmentioning

confidence: 99%

Functional Implication of Nucleolin in the Mouse First Molar Development

Xie

Kobayashi

Kiyoshima

et al. 2007

Journal of Biological Chemistry

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“…52 The transcriptional regulation is mediated by transcription factors, including AP-1, NF-κB, Egr-1, SP-1, GATA 6, and Kruppel-like factor 2 (KLF2), each of which binds to its consensus motif in the gene promoter. [53][54][55][56][57][58] The posttranscriptional regulation is mediated by RNA-binding proteins that bind to mRNA and control its degradation rate. We have shown that the expression of genes encoding GM-CSF and urokinase-type plasminogen activator (uPA) is upregulated by shear stress through mRNA stabilization.…”

Section: Gene Expressionmentioning

confidence: 99%

Vascular Mechanobiology Endothelial Cell Responses to Fluid Shear Stress

Ando

Yamamoto

2009

Circ J

322

138

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lood vessels are not just tubes through which the blood passes, but are active organs with a variety of functions that maintain the homeostasis of the circulatory system. It is a well-established fact that vascular functions are controlled by biochemical mediators, including hormones, cytokines, and neurotransmitters. However, it has recently become apparent that the biomechanical forces generated by blood flow and blood pressure regulate vascular functions. Flowing blood constantly exerts a frictional force, shear stress, on the endothelial cells (ECs) lining blood vessel walls, and the ECs respond to shear stress by changing their morphology, function, and gene expression. EC responses to shear stress are thought to play a critical role in blood-flow-dependent phenomena, including angiogenesis, 1 vascular remodeling, 2 and atherosclerosis. 3 The fact that ECs respond to shear stress indicates that they have the ability to sense shear stress as a signal and transmit it into the interior of the cell. Numerous studies have been devoted to clarifying the mechanisms of shear stress mechanotransduction, and they have demonstrated that multiple signal transduction pathways are activated by shear stress through a variety of membrane molecules and cellular microdomains, including ion channels, G protein, tyrosine kinase receptors, adhesive proteins, caveolae, the cytoskeleton, the glycocalyx, and primary cilia. The mechanisms of shear stress mechanotransduction, however, are not yet fully understood. We review the literature on EC responses to shear stress and the role of their responses in the regulation of the circulatory system, and address the issues of shear stress sensing and signaling mechanisms. EC Responses to Shear StressA considerable amount of information on EC responses to shear stress has accumulated as a result of various in vivo, ex vivo, and in vitro experiments. In vitro experiments in which cultured ECs have been subjected to controlled levels of shear stress in fluid-dynamically designed flow-loading devices, in particular, have enabled analysis of EC responses to shear stress at cellular and molecular levels. [4][5][6][7] In this section, we describe the effects of shear stress on EC morphology, function, and gene expression, and on the differentiation of immature cells, such as endothelial progenitor cells (EPCs) and embryonic stem (ES) cells, into ECs. MorphologyWhen examined in vivo, ECs lining segments of blood vessels in which blood flow is rapid and unidirectional are spindle-shaped and aligned with their long axis parallel to the direction of blood flow, whereas ECs lining segments in which blood flow is turbulent or stagnant are much rounder in shape and do not have a uniform orientation. 8,9 Because of these findings, shear stress is thought to determine the shape and orientation of ECs. When cultured ECs have been J 2009; 73: 1983 -1992)

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Up-regulation of the KLF2 Transcription Factor by Fluid Shear Stress Requires Nucleolin

Cited by 51 publications

References 57 publications

A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

Functional Implication of Nucleolin in the Mouse First Molar Development

Vascular Mechanobiology Endothelial Cell Responses to Fluid Shear Stress

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