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C1q/TNF-related protein 6
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[Plasminogen activator inhibitor-2] This protein is known also as placental plasminogen activator inhibitor (as opposed to endothelial plasminogen activator inhibitor, which is PAI-1). Human epidermal plasminogen activator inhibitor is identical with PAI-2 (Hibino et al, 1988). The protein is known also as monocyte-derived plasminogen activator inhibitor (Antalis et al, 1988) and Monocyte Arg-serpin (Webb et al, 1987) (referring to the fact that PAI-2 is a member of the superfamily of serine proteases with arginine in its reactive center). The gene has been called PLANH2 by Webb et al (1989). Samia et al (1990) have referred to the PAI-2 gene as the urokinase inhibitor gene. PAI-2 has been shown to be identical with placental protein PP10 [placental protein 10] (Kiso et al, 1991). Another designation is Serpin B2.
PAI-2 is is one of the primary extravascular regulators of plasminogen activation. PAI-2 inhibits both tissue plasminogen activator and urokinase-type plasminogen activator (uPA). The human gene structure has been reported by Samia et al (1990). The cDNA has been cloned by Antalis et al (1988).
The protein is found in a variety of cell types: astrocytes, chondrocytes, endothelial cells, eosinophils, fibroblasts, gastric chief cells, granulosa cells, hepatocytes, keratinocyte, Leydig cells, macrophages, melanoma cells, microglia, monocytes, neurons, osteoblasts, osteoclasts, smooth muscle cells, synoviocytes, trophoblast (see individual cell types for references).
PAI-2 exists in an intracellular, nonglycosylated form of 47 kDa and a secreted, glycosylated form of about 60 kDa (Liew et al, 2000; Belin et al, 1989; Bachmann, 1995; Risse et al, 1998; Ye et al, 1989).
PAI-2 has been shown to have a number of intracellular roles: it can alter gene expression, influence the rate of cell proliferation and differentiation, and inhibit apoptosis in a manner independent of urokinase inhibition (Medcalf and Stasinopoulos, 2006). Yu et al (2002) have implicated endogenous PAI-2 as a modulator of monocyte adhesion, proliferation, and differentiation. Hibino et al (1999) have shown that PAI-2 is involved in the regulation of keratinocyte proliferation and differentiation and has an anti-proliferative effect. Lijnen et al (2007) have reported that PAI-2 promotes adipose tissue development in mice via a mechanism independent of its antifibrinolytic effect.
Fan et al (2004) have reported that PAI-2 interacts with pre-mRNA processing factor 8 (PRPF8). Fan et al (2004) have reported that PAI-2 interacts with the proteasome subunit PSMbeta1, which plays a role in NF-kappa-B activation. Zhang et al (2003) have reported that PAI-2 interacts with the interferon regulatory factor IRF3. Darnell et al (2003) have reported that PAI-2 functions as a retinoblastoma protein (Rb)-binding protein and inhibits the turnover of Rb.
Dickinson et al (1995) have implicated PAI-2 in cell death by apoptosis. Dickinson et al (1998) have shown that a structural domain within PAI-2, the C-D interhelical region is important for mediating protection against apoptosis induced by TNF-alpha. Gan et al (1995) have shown that PAI-2 prevents apoptosis of human macrophages infected with Mycobacterium avium. Kasyapa et al (2008) have observed PAI-2-mediated resistance to apoptosis in atypical myeloproliferative disease characterized by expression of the constitutively activated ZNF198/FGFR1 fusion kinase that regulates several STAT transcription factors. Tonnetti et al (2008) have identified PAI-2 as a cell survival factor that regulates the intracellular levels of tumor suppressor retinoblastoma protein Rb and modulates repression of pro-apoptotic signal transduction. Suwa et al (2008) have reported that intraperitoneal injection of recombinant PAI-2 to nude mice bearing human colon cancer xenografts for 6 weeks redcuces tumor size, increases the apoptotic index, and reduces liver metastasis. Ritchie and Fragoyannis (2000) have shown that inhibition of PAI-2 expression in monocytes is not involved in the inhibition of cell death by apoptosis.
Antalis et al (1998) have shown that intracellular, but not extracellular, PAI-2 protects cells from the rapid cytopathic effects of alphavirus infection. This protection does not appear to be related to an effect on apoptosis but is associated with a PAI-2-mediated induction of constitutive low-level production of IFN-alpha and IFN-beta and IFN-stimulated gene factor 3 (ISGF3) activation, which primes the cells for rapid induction of antiviral genes. Darnell et al (2006) have shown that HIV-1 infection and gp120 treatment of human peripheral blood mononuclear cells induces expression of PAI-2 and that PAI-2 is an inducible host factor that significantly promotes HIV-1 replication.
Dougherty et al (1999) have generated knock-out mice lacking expression of PAI-2. These mice develop normally and are indistinguishable from wild-type mice in terms of survival, fertility, responses to bacterial infection, and endotoxin infusion. Monocyte recruitment into the peritoneum after thioglycollate injection appears normal. Epidermal wound healing is not affected.
Transgenic overexpression of PAI-2 in keratinocytes has been shown to promote the development and progression of epidermal papillomas in a manner that does not involve inhibition of its extracellular target protease, uPA, but appears to be related to an inhibition of apoptosis (Zhou et al, 2001).
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