scholarly journals Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2

2014 ◽  
Vol 211 (3) ◽  
pp. 395-404 ◽  
Author(s):  
Chen Wang ◽  
Lingfeng Qin ◽  
Thomas D. Manes ◽  
Nancy C. Kirkiles-Smith ◽  
George Tellides ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mammalian Target Of Rapamycin ◽  
Functional Change ◽  
Target Of Rapamycin ◽  
Vascular Cell Adhesion ◽  
Potential Therapeutic Target ◽  
Tnf Induction ◽  
Cell Adhesion Molecule 1 ◽  
Mediate Inflammation

Recruitment of circulating leukocytes into inflamed tissues depends on adhesion molecules expressed by endothelial cells (ECs). Here we report that rapamycin pretreatment reduced the ability of TNF-treated ECs to capture T cells under conditions of venular flow. This functional change was caused by inhibition of TNF-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and could be mimicked by knockdown of mammalian target of rapamycin (mTOR) or rictor, but not raptor, implicating mTORC2 as the target of rapamycin for this effect. Mechanistically, mTORC2 acts through Akt to repress Raf1-MEK1/2-ERK1/2 signaling, and inhibition of mTORC2 consequently results in hyperactivation of ERK1/2. Increased ERK1/2 activity antagonizes VCAM-1 expression by repressing TNF induction of the transcription factor IRF-1. Preventing activation of ERK1/2 reduced the ability of rapamycin to inhibit TNF-induced VCAM-1 expression. In vivo, rapamycin inhibited mTORC2 activity and potentiated activation of ERK1/2. These changes correlated with reduced endothelial expression of TNF-induced VCAM-1, which was restored via pharmacological inhibition of ERK1/2. Functionally, rapamycin reduced infiltration of leukocytes into renal glomeruli, an effect which was partially reversed by inhibition of ERK1/2. These data demonstrate a novel mechanism by which rapamycin modulates the ability of vascular endothelium to mediate inflammation and identifies endothelial mTORC2 as a potential therapeutic target.

scholarly journals Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and gamma-irradiated mice

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 73-82 ◽  
Author(s):  
K Jacobsen ◽  
J Kravitz ◽  
PW Kincade ◽  
DG Osmond
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Cell Adhesion Molecule ◽  
Vascular Cell Adhesion ◽  
Vascular Cell ◽  
Sinusoidal Endothelium ◽  
Reticular Cells ◽  
Cell Adhesion Molecule 1

Cell adhesion molecules (CAMs) play a key role in interactions between stromal and hematopoietic cells in bone marrow (BM) and in cell traffic through vascular endothelium. To examine the identity of CAMs involved in these processes in mouse BM, we have investigated the in vivo expression of vascular cell adhesion molecule-1 (VCAM-1) and its counter-receptor, very late antigen-4 (VLA-4). Radioiodinated monoclonal antibodies (MoAbs) detecting VLA-4 and VCAM-1 were injected intravenously. Antibody binding was detected in BM by light and electron microscope radioautography. VCAM-1 labeling was restricted to stromal reticular cells and endothelial cells lining BM sinusoids. VCAM- 1+ reticular cells formed patchy concentrations, especially in subosteal regions, associated with lymphoid, granulocytic, and erythroid cells. After gamma-irradiation to deplete hematopoietic cells, reticular cells and endothelial cells all showed VCAM-1 labeling in apparently increased intensity. VLA-4 labeling was shown by undifferentiated blast cells and lymphohematopoietic cells both in BM cell suspensions and in vivo, especially at reticular cell contact points. The results demonstrate that VCAM-1 is expressed in vivo by certain BM reticular cells, suggesting that the molecule mediates adhesion to multiple lineages of lymphohematopoietic cells. The finding that VCAM-1 is also expressed constitutively by BM sinusoidal endothelium, unlike its inductive expression by endothelia elsewhere, suggests that VCAM-1 and VLA-4 may be involved in regulating the normal cell traffic between BM and the blood stream.

scholarly journals Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and gamma-irradiated mice

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 73-82 ◽  
Author(s):  
K Jacobsen ◽  
J Kravitz ◽  
PW Kincade ◽  
DG Osmond
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Cell Adhesion Molecule ◽  
Vascular Cell Adhesion ◽  
Vascular Cell ◽  
Sinusoidal Endothelium ◽  
Reticular Cells ◽  
Cell Adhesion Molecule 1

Abstract Cell adhesion molecules (CAMs) play a key role in interactions between stromal and hematopoietic cells in bone marrow (BM) and in cell traffic through vascular endothelium. To examine the identity of CAMs involved in these processes in mouse BM, we have investigated the in vivo expression of vascular cell adhesion molecule-1 (VCAM-1) and its counter-receptor, very late antigen-4 (VLA-4). Radioiodinated monoclonal antibodies (MoAbs) detecting VLA-4 and VCAM-1 were injected intravenously. Antibody binding was detected in BM by light and electron microscope radioautography. VCAM-1 labeling was restricted to stromal reticular cells and endothelial cells lining BM sinusoids. VCAM- 1+ reticular cells formed patchy concentrations, especially in subosteal regions, associated with lymphoid, granulocytic, and erythroid cells. After gamma-irradiation to deplete hematopoietic cells, reticular cells and endothelial cells all showed VCAM-1 labeling in apparently increased intensity. VLA-4 labeling was shown by undifferentiated blast cells and lymphohematopoietic cells both in BM cell suspensions and in vivo, especially at reticular cell contact points. The results demonstrate that VCAM-1 is expressed in vivo by certain BM reticular cells, suggesting that the molecule mediates adhesion to multiple lineages of lymphohematopoietic cells. The finding that VCAM-1 is also expressed constitutively by BM sinusoidal endothelium, unlike its inductive expression by endothelia elsewhere, suggests that VCAM-1 and VLA-4 may be involved in regulating the normal cell traffic between BM and the blood stream.

Vascular Cell Adhesion Molecule-1 Expression in Endothelial Cells Exposed to Physiological Coronary Wall Shear Stresses

2009 ◽  
Vol 131 (8) ◽  
Author(s):  
Lucy M. O'Keeffe ◽  
Gordon Muir ◽  
Anna V. Piterina ◽  
Tim McGloughlin
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Shear Stresses ◽  
Disease Development ◽  
Vascular Cell Adhesion ◽  
Vascular Cell ◽  
Cell Adhesion Molecule 1

Atherosclerosis is consistently found in bifurcations and curved segments of the circulatory system, indicating disturbed hemodynamics may participate in disease development. In vivo and in vitro studies have shown that endothelial cells (ECs) alter their gene expression in response to their hemodynamic environment, in a manner that is highly dependent on the exact nature of the applied forces. This research exposes cultured ECs to flow patterns present in the coronary arterial network, in order to determine the role of hemodynamic forces in plaque initiation. Vascular cell adhesion molecule-1 (VCAM-1) was examined as an indicator of plaque growth, as it participates in monocyte adhesion, which is one of the initial steps in the formation of fatty lesions. The hemodynamics of a healthy right and left coronary artery were determined by reconstructing 3D models from cineangiograms and employing computational fluid dynamic models to establish physiological coronary flow patterns. Wall shear stress (WSS) profiles selected from these studies were applied to ECs in a cone and plate bioreactor. The cone and plate system was specifically designed to be capable of reproducing the high frequency harmonics present in physiological waveforms. The shear stresses chosen represent those from regions prone to disease development and healthier arterial segments. The levels of the transcriptional and cell surface anchored VCAM-1 were quantified by flow cytometry and real time RT-PCR over a number of timepoints to obtain a complete picture of the relationship between this adhesion molecule and the applied shear stress. The WSS profiles from regions consistently displaying a higher incidence of plaques in vivo, induced greater levels of VCAM-1, particularly at the earlier timepoints. Conversely, the WSS profile from a straight section of vessel with undisturbed flow indicated no upregulation in VCAM-1 and a significant downregulation after 24 h, when compared with static controls. Low shear stress from the outer wall of a bifurcation induced four times the levels of VCAM-1 messenger ribonucleic acid (mRNA) after four hours when compared with levels of mRNA induced by WSS from a straight arterial section. This shear profile also induced prolonged expression of the surface protein of this molecule. The current study has provided insight into the possible influences of coronary hemodynamics on plaque localization, with VCAM-1 only significantly induced by the WSS from disease prone regions.

scholarly journals Functional analysis of the human vascular cell adhesion molecule 1 promoter.

1992 ◽  
Vol 176 (6) ◽  
pp. 1583-1593 ◽  
Author(s):  
A S Neish ◽  
A J Williams ◽  
H J Palmer ◽  
M Z Whitley ◽  
T Collins
Keyword(s):  
Endothelial Cells ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Core Promoter ◽  
Flanking Sequence ◽  
Vascular Cell Adhesion ◽  
Nf Kappa B ◽  
Vascular Cell ◽  
The Core ◽  
Cell Adhesion Molecule 1

The vascular cell adhesion molecule 1 (VCAM-1) is a 110-kD member of the immunoglobulin gene superfamily expressed on the surface of interleukin 1 beta- or tumor necrosis factor alpha (TNF)-stimulated endothelial cells. The cell surface protein functions as an inducible adhesion receptor for circulating mononuclear leukocytes and some tumor cells. We have previously characterized the genomic organization of the VCAM1 gene and described its chromosomal localization. In this report, the promoter of the VCAM1 gene is characterized. New transcription of the VCAM1 gene occurred when endothelial cells were treated with TNF. Fusion plasmids containing the 5' flanking sequence of the VCAM1 gene and the chloramphenicol acetyltransferase reporter gene were used to identify cis-acting sequences that direct the cytokine-induced transcription. When transfected into bovine aortic endothelial cells, constructs containing 755 bp of the 5' flanking sequence were induced by TNF. Within the cytokine-responsive region of the core promoter were functional NF-kappa B and GATA elements. Upstream of the core promoter, the VCAM1 5' flanking sequence contained a negative regulatory activity. NF-kappa B-mediated activation of VCAM1 gene expression may lead to endothelial expression of a mononuclear leukocyte adhesion molecule associated with initial events in the development of an atherosclerotic lesion.

scholarly journals SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors

2019 ◽  
Vol 5 (9) ◽  
pp. eaax6352 ◽  
Author(s):  
Akihiro Yoshida ◽  
Yiwen Bu ◽  
Shuo Qie ◽  
John Wrangle ◽  
E. Ramsay Camp ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Fragile X ◽  
Acquired Resistance ◽  
Mammalian Target Of Rapamycin ◽  
Cyclin Dependent Kinase ◽  
Solute Carrier Family ◽  
Potential Therapeutic Target ◽  
Mtorc1 Signaling ◽  
Solute Carrier

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X mental retardation syndrome–associated protein 1 overexpression, which promotes SLC36A1 translation and subsequently mTORC1. Last, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo, providing an important avenue for improved therapeutic intervention in aggressive melanoma.

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