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TNF-Convertase Enzyme from Human Arthritis-Affected Cartilage: Isolation of cDNA by Differential Display,

Summary: TNF- Convertase Enzyme from Human Arthritis-Affected
Cartilage: Isolation of cDNA by Differential Display,
Expression of the Active Enzyme, and Regulation of TNF- 1
Indravadan R. Patel,2
* Mukundan G. Attur,2
* Rajesh N. Patel,* Steven A. Stuchin,
Ruben A. Abagyan,
Steven B. Abramson,*
and Ashok R. Amin3
A snake venom-like protease isolated by a differential display screen between normal and osteoarthritis (OA)-affected cartilage
(designated as cSVP) has a cDNA sequence identical to TNF- convertase enzyme (TACE). TACE shows the presence of an
unknown prodomain, a cysteine switch, a catalytic domain, a zinc binding region, a disintegrin region, an EGF-like domain, a
transmembrane domain, and a unique cytoplasmic region. A TACE construct harboring the signal prodomain catalytic
region (TACE-SPC DETCy), expressed in baculovirus could cleave preferentially ( 12-fold) the TNF-specific peptide over the
matrix metalloproteases peptide in vitro. This recombinant protein also cleaved the natural substrate GST-ProTNF- to TNF-
(17 kDa) in vitro. The mRNA for TACE, which is broadly distributed and differentially expressed in a variety of human tissues,
is up-regulated in arthritis-affected cartilage, but not normal cartilage. OA-affected cartilage also expressed TNF- mRNA that
was not detected in normal cartilage. The OA-affected cartilage (in explant assays) spontaneously released TNF- and IL-8 in ex
vivo conditions. Addition of TNF- R fused to IgG Fc fragment (TNF- R:Fc) in the presence or absence of soluble IL-1R (with


Source: Abagyan, Ruben - School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego


Collections: Biology and Medicine