Proteolytic inactivation of human α<sub>1</sub> antitrypsin by human stromelysin

Winyard, Paul G.; Zhi, Zhang; Chidwick, Keith; Blake, David R.; Carrell, Robin W.; Murphy, Gillian

doi:10.1016/0014-5793(91)80258-5

Cited by 63 publications

(19 citation statements)

References 12 publications

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“…Matrix Metalloproteases is a family of proteins that are mainly involved in the breakdown of extracellular matrix for both normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, and disease processes, such as asthma and cancer metastasis. The MMP family currently consists of 27 members and many, including MMP-1, -3, -7, -8, -11, -26, effectively cleave AAT [18][19][20][21][22][23]. Among these MMPS, MMP-7 and MMP-26 are of particular interest.…”

Section: C-42 Can Be Generated In Vitro By Action Of Mmp-7mentioning

confidence: 99%

A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient

Zhou

Trock

Tsangaris

et al. 2009

Breast Cancer Res Treat

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By comparison of mass spectra from a small cohort of nipple aspiration fluids (NAF), we previously discovered a panel of five candidate breast cancer biomarkers among them an unidentified 4.7 kD peptide BF5. The purposes of the present study were to verify the presence of BF5 in an independent cohort; to determine the protein identity of BF5; and to provide insight into the biology of BF5 production and elevation in tumor-associated NAF. We prospectively collected bilaterally matched NAF from patients with unilateral Stage I/II breast cancer (IBC-31), ductal carcinoma in situ (DCIS-6), atypical ductal hyperplasia (ADH-5), and presumed healthy women who came to routine mammography and had a normal exam (31). Following the consolidation of its cancer-associated expression on SELDI-mass spectrometry, BF5 was isolated by gel electrophoresis and sequenced by tandem mass spectrometry. BF5 was elevated in 15-25% of women with IBC, DCIS, or ADH vs. 0% of controls. This elevation was restricted to the affected breasts. BF5 was identified as 41/42-aa C-terminal peptide of alpha1-antitrypsin (AAT), the principle inhibitor of serine protease neutrophile elastase. The full length AAT showed a consistent expression pattern as C-41/42, and C-41/42 can be generated in vitro by MMP-7 cleavage. In conclusion, elevated C-41/42 is likely the result of elevated AAT synthesis, and the activity of specific MMPs present within the tumor. As other C-terminal fragments of AAT are reported to function as tumor-derived suppressors to the host immune-system, elevated C-41/42 may also be predictive of a poor outcome.

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Section: C-42 Can Be Generated In Vitro By Action Of Mmp-7mentioning

confidence: 99%

A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient

Zhou

Trock

Tsangaris

et al. 2009

Breast Cancer Res Treat

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“…Our understanding of AAT function has been derived primarily from studies of native, functionally active AAT, while possible biological roles of postcleavage, noninhibitory forms of AAT and its degradation products have received little attention. These latter occur when AAT forms an inhibitor complex with serine protease or when it is cleaved in its reactive site loop by nontarget proteinases, which do not lead to formation of stable inhibitor complexes (Michaelis et al 1990;Winyard et al 1991). For example, it was recently shown that induction of connective tissue breakdown in rats results in a four-to eightfold increase in macrophage and AAT levels, with some of the AAT appearing as protease cleavage fragments (Zay et al 1999).…”

Section: Introductionmentioning

confidence: 97%

Fibrillogenic C-terminal fragment of alpha-1-antitrypsin activates human monocytes via oxidative mechanisms

2001

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Production of alpha-1-antitrypsin by human monocytes is an important factor in controlling tissue damage by proteases in the microenvironment of inflammation. Increases of four- to eightfold in levels of native and fragmented forms of alpha-1-antitrypsin have been detected in inflammatory loci in vivo. In this study we have extended our previous observation that the carboxyl-terminal peptide (C-36) of alpha-1-antitrypsin produced by specific proteinase cleavage, when added in its fibrillar form at concentrations of 5 microM or more to monocytes in culture, induces cytotoxic effects. Experiments with synthetic amyloid-forming peptides suggest fibril cytotoxicity to be mediated via a common oxidative stress mechanism. We undertook to determine whether C-36 fibril cytotoxicity also involves this common pathway. Monocytes stimulated with C-36 fibrils for 1 h showed significant elevation in monocyte chemoattractant protein-1 expression, induced reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, increased intracellular lipid peroxidation, altered mitochondrial membrane potential, and increased cytosolic cytochrome c and caspase-3 activity. Treatment of monocytes with C-36 fibrils after 24 h also resulted in increased cytosolic cathepsin D activity, suggesting that lysosomes may also be destabilized over longer periods of time. In contrast, native alpha-1-antitrypsin only showed concentration and time-dependent effects on chemoattractant protein-1 expression, and these appear to be independent of oxidative stress. These results indicate that the cytotoxicity of the fibrillar fragment is mediated via oxidative mechanisms and support important multiple roles for native and also for cleaved forms of alpha-1-antitrypsin in monocyte recruitment and activation during inflammatory processes such as atherosclerosis.

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“…In vitro, ROS have been shown to activate latent metalloproteinases, such as human neutrophil collagenase [22]. Since a number of metalloproteinases are capable of degrading a,AT [11,22], ROS may indirectly promote the proteolytic inactivation of cx,AT and cartilage destruction. a,AT proteolysis due to ROS-mediated metalloproteinase activation may occur over a longer time-course than that studied here.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of synovial fluid α₁‐antitrypsin by exercise of the inflamed rheumatoid joint

et al. 1993

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α1‐Antitrypsin (α1AT) is known to be oxidised by reactive oxygen species both in vitro and in vivo, leading to its inactivation. We report here that synovial fluid (SF) α1AT is inactivated during exercise of the knee‐joints of rheumatoid arthritis (RA) patients. Sequential SF sampling from exercised RA patients showed a marked decrease in the mean activity of α1AT after exercise with no change in the molecular forms of α1AT. No such inactivation was found in the control (continuously resting) RA patients. We suggest that oxidation may contribute to α1AT inactivation as a consequence of ‘hypoxic‐reperfusion’ injury after exercise of the inflamed joint.

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Proteolytic inactivation of human α₁ antitrypsin by human stromelysin

Cited by 63 publications

References 12 publications

A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient

A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient

Fibrillogenic C-terminal fragment of alpha-1-antitrypsin activates human monocytes via oxidative mechanisms

Inactivation of synovial fluid α₁‐antitrypsin by exercise of the inflamed rheumatoid joint

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Proteolytic inactivation of human α1 antitrypsin by human stromelysin

Cited by 63 publications

References 12 publications

A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient

A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient

Fibrillogenic C-terminal fragment of alpha-1-antitrypsin activates human monocytes via oxidative mechanisms

Inactivation of synovial fluid α1‐antitrypsin by exercise of the inflamed rheumatoid joint

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Proteolytic inactivation of human α₁ antitrypsin by human stromelysin

Inactivation of synovial fluid α₁‐antitrypsin by exercise of the inflamed rheumatoid joint