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Overexpression of tissue inhibitors of metalloproteinase 2 up-regulates NF-kappaB activity in melanoma cells.

ABSTRACT: Matrix Metalloproteinase functions in the remodeling of the extracellular matrix that is integral for many normal and pathological processes such as morphogenesis, angiogenesis, tissue repair, and tumor invasion. The tissue inhibitor of the metalloproteinase family including the tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates the activity of multifunctional metalloproteinase. It is known that IL-8, the target gene of NF-kappaB pathway, increases in the melanoma cells. However, it is not clear whether the TIMP-2 expression regulates the NF-kappaB pathway. In this study, we have used stable melanoma cell lines, parental A2058, A2058T2-1 overexpressing TIMP-2, and A2058T2R-7 underexpressing TIMP-2, to determine the TIMP-2 regulation of the NF-kappaB activity.We found that the IL-8 secretion and IL-8 mRNA expression significantly increased in the A2058T2-1 overexpressing TIMP-2. TIMP-2 overexpressed cells had the lower basal level of IkappaBalpha, the inhibitor of NF-kappaB, compared to the parental A2058 cells. The transcriptional NF-kappaB activity was increased by the TIMP-2 overexpression. In contrast, A2058T2R-7 underexpressing TIMP-2 had the similar NF-kappaB activity as that in the parental A2058 cell. The apoptotic cells induced by TNF were less in TIMP-2 over-expression cells compared to those in the parental A2058 cells. TIMP-2 over-expression was able to protect cells from apoptosis.Our data demonstrate that the expression level of TIMP-2 protein can directly modulate the NF-kappaB pathway in human melanoma cells.

SUBMITTER: Sun J

PROVIDER: S-EPMC2720935 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Overexpression of tissue inhibitors of metalloproteinase 2 up-regulates NF-kappaB activity in melanoma cells.

Sun Jun J Stetler-Stevenson William G WG

Journal of molecular signaling 20090723

<h4>Background</h4>Matrix Metalloproteinase functions in the remodeling of the extracellular matrix that is integral for many normal and pathological processes such as morphogenesis, angiogenesis, tissue repair, and tumor invasion. The tissue inhibitor of the metalloproteinase family including the tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates the activity of multifunctional metalloproteinase. It is known that IL-8, the target gene of NF-kappaB pathway, increases in the melanoma cell ...[more]

PMID: 19627587

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Project description:Initial Ca2+-dependent contraction of the intestinal smooth muscle mediated by G(q)-coupled receptors is attenuated by RGS4 (regulator of G-protein signalling 4). Treatment of colonic muscle cells with IL-1beta (interleukin-1beta) inhibits acetylcholine-stimulated initial contraction through increasing the expression of RGS4. NF-kappaB (nuclear factor kappaB) signalling is the dominant pathway activated by IL-1beta. In the present study we show that RGS4 is a new target gene regulated by IL-1beta/NF-kappaB signalling. Exposure of cultured rabbit colonic muscle cells to IL-1beta induced a rapid increase in RGS4 mRNA expression, which was abolished by pretreatment with a transcription inhibitor, actinomycin D, implying a transcription-dependent mechanism. Existence of the canonical IKK2 [IkappaB (inhibitor of NF-kappaB) kinase 2]/IkappaBalpha pathway of NF-kappaB activation induced by IL-1beta in rabbit colonic muscle cells was validated with multiple approaches, including the induction of reporter luciferase activity and endogenous NF-kappaB-target gene expression, NF-kappaB-DNA binding activity, p65 nuclear translocation, IkappaBalpha degradation and the phosphorylation of IKK2 at Ser(177/181) and p65 at Ser(536). RGS4 up-regulation by IL-1beta was blocked by selective inhibitors of IKK2, IkappaBalpha or NF-kappaB activation, by effective siRNA (small interfering RNA) of IKK2, and in cells expressing either the kinase-inactive IKK2 mutant (K44A) or the phosphorylation-deficient IkappaBalpha mutant (S32A/S36A). An IKK2-specific inhibitor or effective siRNA prevented IL-1beta-induced inhibition of acetylcholine-stimulated PLC-beta (phopsholipase C-beta) activation. These results suggest that the canonical IKK2/IkappaBalpha pathway of NF-kappaB activation mediates the up-regulation of RGS4 expression in response to IL-1beta and contributes to the inhibitory effect of IL-1beta on acetylcholine-stimulated PLC-beta-dependent initial contraction in rabbit colonic smooth muscle.

Dataset Information

Overexpression of tissue inhibitors of metalloproteinase 2 up-regulates NF-kappaB activity in melanoma cells.

Publications

Overexpression of tissue inhibitors of metalloproteinase 2 up-regulates NF-kappaB activity in melanoma cells.

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