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Oxidative stress and protein sheddin...

University of Louisville.

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Oxidative stress and protein shedding: Pervanadate-induced shedding of intercellular adhesion molecule (ICAM)-1.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Oxidative stress and protein shedding: Pervanadate-induced shedding of intercellular adhesion molecule (ICAM)-1./
Author:	Essick, Eric E.
Description:	177 p.
Notes:	Source: Dissertation Abstracts International, Volume: 69-10, Section: B, page: 5957.
Contained By:	Dissertation Abstracts International69-10B.
Subject:	Biology, Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3333835
ISBN:	9780549861843

Oxidative stress and protein shedding: Pervanadate-induced shedding of intercellular adhesion molecule (ICAM)-1.
Essick, Eric E.

Oxidative stress and protein shedding: Pervanadate-induced shedding of intercellular adhesion molecule (ICAM)-1. - 177 p.

Source: Dissertation Abstracts International, Volume: 69-10, Section: B, page: 5957.

Thesis (Ph.D.)--University of Louisville, 2008.

The long term purpose of this research looks to provide a better understanding of inflammatory diseases for the development of therapeutic means of combating vascular disease.

ISBN: 9780549861843Subjects--Topical Terms:

1017816
Biology, Physiology.

Oxidative stress and protein shedding: Pervanadate-induced shedding of intercellular adhesion molecule (ICAM)-1.
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020 $a 9780549861843
035 $a (UMI)AAI3333835
035 $a AAI3333835
040 $a UMI $c UMI
100 1 $a Essick, Eric E. $3 1021790
245 1 0 $a Oxidative stress and protein shedding: Pervanadate-induced shedding of intercellular adhesion molecule (ICAM)-1.
300 $a 177 p.
500 $a Source: Dissertation Abstracts International, Volume: 69-10, Section: B, page: 5957.
502 $a Thesis (Ph.D.)--University of Louisville, 2008.
520 $a The long term purpose of this research looks to provide a better understanding of inflammatory diseases for the development of therapeutic means of combating vascular disease.
520 $a The endothelial cells (EC, see appendix A for common abbreviations) lining the blood vessels maintain a non-adhesive vascular compartment (1,2). Inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and lipopolysaccharide (LPS) released from damaged and/or inflamed EC lead to up-regulation of cell surface adhesion molecules such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) rendering the endothelium susceptible to adhesive interactions with circulating integrin expressing leukocytes and their subsequent transmigration to areas of inflammation (3-5). However, unregulated and persistent leukocyte infiltration results in tissue damage as manifested in diseases such as atherosclerosis, myocardial infarction and stroke (6). In several vascular disease states such as chronic inflammation and oxidative stress, ICAM-1 and VCAM-1 become proteolytically cleaved at the ectodomain, releasing the soluble form of the proteins (sICAM-1, sVCAM-1), both common inflammatory markers (7,8). Our studies and those of others indicate that tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) mediates the cleavage of both ICAM-1 and VCAM-1 (9). In addition, recent studies indicate that membrane-type matrix metalloproteinases (MT-MMP) also mediate the cleavage of these adhesion receptors. Furthermore, since ICAM-1 is known to transmit robust intercellular signals, I sought to explore the signaling and enzymatic effects on ICAM-1 cleavage upon treatment with pervanadate, a complex of H2O2 and the phosphate analog, vanadate. Pervanadate is known to cause inhibition of protein tyrosine phosphatases, one of the many effects oxidative stress has on cellular function. I hypothesize that inhibition of protein tyrosine phosphatases occurring during conditions of oxidative stress mediated by pervanadate, induces ectodomain shedding of ICAM-1 by increasing activation of the MAPK/ERK1/2 signaling pathway, which in turn regulates a specific zinc-dependent metalloproteinase that cleaves ICAM-1. Based on this hypothesis, I have formulated the following aims: Aim 1. To determine if treatment of EC and 293 human embryonic kidney (HEK) cells with pervanadate induces ectodomain shedding of ICAM-1, and identify the functional consequences of ICAM-1 shedding (leukocyte adhesion and endothelial migration). Aim 2. To determine the intercellular signaling mechanism involved in pervanadate-induced ectodomain shedding of ICAM-1 from either EC and/or 293 HEK cells. Aim 3. To determine the specific proteolytic enzyme(s) involved in pervanadate-induced ectodomain shedding of ICAM-1 from either EC and/or 293 HEK cells.
520 $a My data indicates that pervanadate increases cleavage of the ICAM-1 ectodomain, which appears to inhibit leukocyte adhesion as well as endothelial cell migration. Moreover, this cleavage is dependent upon a specific tyrosine residue located in the cytoplasmic-tail (Y485) domain of ICAM-1, suggesting the involvement tyrosine phosphorylation and subsequent activation of intercellular signaling cascades. In addition, pervanadate leads to an increased phosphorylation of extracellular-signal regulated kinase (ERK) which correlates to ICAM-1 cleavage, implicating the role of this particular mitogen activated protein kinase (MAPK) signaling cascade in this mode of cleavage. Finally, by employing specific tissue inhibitors of metalloproteinases (TIMPs) and small interfering (si) RNA designed to knock down endopeptidase expression, I found that this cleavage is mediated by membrane type-1 matrix metalloproteinase (MT1-MMP). Immunocolocalization and confocal microscopy provide evidence that ICAM-1 and MT1-MMP colocalize at the cellular surface following pervanadate treatment, further implicating the involvement of MT1-MMP in this mode of ICAM-1 shedding. Taken together, I conclude that conditions of oxidative stress induced by pervanadate leads to activation of the ERK signaling pathway, which in turn activates MT1-MMP shedding of sICAM-1 ectodomain.
590 $a School code: 0110.
650 4 $a Biology, Physiology. $3 1017816
650 4 $a Health Sciences, Immunology. $3 1017716
690 $a 0719
690 $a 0982
710 2 $a University of Louisville. $3 1017614
773 0 $t Dissertation Abstracts International $g 69-10B.
790 $a 0110
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3333835