Redox-dependent Matrix Metalloproteinase-1 Expression Is Regulated by JNK through Ets and AP-1 Promoter Motifs

Abstract

present study, we investigate the molecular mechanisms involved in the H 2 O 2 -mediated induction of MMP-1. Mutational analysis of an MMP-1 promoter indicates that both the single nucleotide polymorphism creating an Ets binding site at ؊1607 and a proximal AP-1 site at ؊1602 are required for maximal H 2 O 2 -dependent transcription. The redox-sensitive MMP-1 protein expression requires activation of both ERK1/2 and JNK pathways. Importantly, JNK signaling is largely responsible for the H 2 O 2 sensitivity of the MMP-1 promoter, whereas ERK1/2 contributes to both its basal and H 2 O 2 dependence. H 2 O 2 control of Ets-1 expression was ERK1/2-dependent whereas that of c-Jun requires both ERK1/2 and JNK signaling. Chromatin immunoprecipitation assays indicate that binding of the histone acetyltransferase, p300, and the transcription factors Ets-1 and c-Jun to the MMP-1 promoter is redox sensitive. The redox sensitivity of MMP-1 expression is also associated with an increase in the abundance of oxidatively inactivated protein-tyrosine phosphatases. Targeted cytosolic or mitochondrial scavenging of H 2 O 2 prevented all of the aforementioned signals. These studies provide substantial insight into the mechanisms underlying the redox-dependent control of MMP-1 and may lead to the development of novel targeted antioxidant-based inhibitory therapies for controlling MMP-1 expression during degenerative disease processes. The matrix metalloproteinase (MMP)5 family consists of at least 25 zincdependent proteases that degrade multiple components of the extracellular matrix (ECM) (1). Under normal physiological conditions MMPs are important for development and wound healing; however, their augmented expression is associated with numerous disease pathologies (2). For example, MMPs are important at many stages of metastasis and the high level expression of the MMP family member, MMP-1, has been linked to poor prognosis in many types of cancers (3-9).Within the MMP-1 promoter, Brinckerhoff and co-workers (10) identified a single nucleotide polymorphism (SNP) guanine insertion at Ϫ1607 (1G 3 2G) base pairs that enhances the basal rate of transcription by creation of an Ets binding domain. Ets transcription factors include a large family of helix-turn-helix proteins (11) that normally do not bind DNA alone, but preferentially form coactivator complexes with transcription factors, like activator protein-1 (AP-1) (12). The proto-oncoproteins Fos and Jun, which comprise the AP-1 complex, can homo-or heterodimerize and bind its cognate consensus sequence (TGACTCA) in the regulatory domains of many genes including various MMP family members (13). Both Ets and AP-1 play a critical role in regulating the expression of various MMP family members, particularly that of MMP-1 (14). The MMP-1 SNP is associated with a higher risk of metastasis in patients with a variety of distinct cancers (15-19). More striking is the finding that both Ets-1 and MMP-1 immunoreactivity is high in stromal tissue adjacent to the leading edge of several tumor t...

Delineating the Molecular Mechanism behind Regulation of Spermatogenesis by Selenium: Involvement of Mitogen Activated Protein Kinase; JNK

“…In addition, it has been recently suggested that ROS produced by cytokines and nitric oxide would be a second messenger to stimulate JNK, and some low molecular weight G proteins (such as p21rea, Rac1 and CDC42) might be sensors in JNK activation for ROS [45]. Upregulation of MnSOD as reported in the present study leading to accumulation of H 2 O 2 could also lead to phosphorylation and activation of JNK as reported by other studies [46].…”

Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators

“…Indeed, adjacent AP1 and Ets motifs in promoters can form so-called Ras-responsive elements that mediate cellular responses to Ras-MAPK signaling (McCarthy et al, 1997;Westwick et al, 1994;Yang et al, 1996). Similar AP1 and Ets motifs have been detected within the promoters of Mmp genes, where they play a major role in regulating expression of these genes (Kapila et al, 2009;Nelson et al, 2006;Watabe et al, 1998). Several Mmp genes demonstrate dramatically increased expression in E18.5 BT skin, and we have previously demonstrated upregulation of many Mmp genes in epidermis of BT mice induced at an adult age (Nagarajan et al, 2009).…”

Trolox induces inhibition of cell proliferation and apoptosis in human colon cancer cells

“…5,7,, an analog of vitamin E has been widely investigated for its role in the inhibition of oxidative stress or damage in cancer cells (Lúcio et al, 2009;Barclay et al, 1995;Forrest et al, 1994). Further, its effect has also been investigated in induction of antioxidative effect through expression of MMP in inflammatory diseases and cancers (Haug et al, 2004;Nelson et al, 2006). It has been reported that MMPs play a vital role in the process of human lung and cervical cancer metastasis (Nelson et al, 2000;Sheu et al, 2003).…”