Ro 09-2210 Exhibits Potent Anti-proliferative Effects on Activated T Cells by Selectively Blocking MKK Activity

Dh, Williams; Se, Wilkinson; Purton, Tracey; Lamont, Alan; Flotow, Horst; Ej, Murray

doi:10.1021/bi972914c

Cited by 56 publications

(32 citation statements)

References 50 publications

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“…Two compounds, Ro092210 and L783277, with very similar structures to 5Z-7-oxozeaenol were previously demonstrated to inhibit MEK kinase activity (17,18). We examined the effect of 5Z-7-oxozeaenol on purified rat MEK1 kinase activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Resorcylic Acid Lactone, 5Z-7-Oxozeaenol, Prevents Inflammation by Inhibiting the Catalytic Activity of TAK1 MAPK Kinase Kinase

Ninomiya‐Tsuji

Kajino

Ono³

et al. 2003

Journal of Biological Chemistry

391

348

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TAK1, a member of the mitogen-activated kinase kinase kinase (MAPKKK) family, participates in proinflammatory cellular signaling pathways by activating JNK/p38 MAPKs and NF-B. To identify drugs that prevent inflammation, we screened inhibitors of TAK1 catalytic activity. We identified a natural resorcylic lactone of fungal origin, 5Z-7-oxozeaenol, as a highly potent inhibitor of TAK1. This compound did not effectively inhibit the catalytic activities of the MEKK1 or ASK1 MAPKKKs, suggesting that 5Z-7-oxozeaenol is a selective inhibitor of TAK1. In cell culture, 5Z-7-oxozeaenol blocked interleukin-1-induced activation of TAK1, JNK/ p38 MAPK, IB kinases, and NF-B, resulting in inhibition of cyclooxgenase-2 production. Furthermore, in vivo 5Z-7-oxozeaenol was able to inhibit picryl chlorideinduced ear swelling. Thus, 5Z-7-oxozeaenol blocks proinflammatory signaling by selectively inhibiting TAK1 MAPKKK.TAK1 is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) 1 family that phosphorylates and activates MKK3, MKK4, MKK6, and MKK7 MAPKKs, which in turn activate the c-Jun N-terminal kinase (JNK) and p38 MAPKs (1-3). We have recently demonstrated that TAK1 also activates IB kinases (IKKs), ultimately leading to activation of the transcription factor NF-B (4). TAK1 participates in proinflammatory cellular signaling pathways such as the interleukin-1 (IL-1) pathway by activating both JNK/p38 MAPKs and IKKs. Exposure of cells to IL-1 induces the interaction between endogenous TAK1 and TRAF6 (tumor necrosis factor (TNF) receptor-associated factor 6), a molecule essential for IL-1 activation of both JNK/p38 and NF-B. This interaction in turn leads to TAK1 activation. We have previously identified two TAK1-binding proteins, TAB1 and TAB2 (5, 6). When ectopically co-expressed, TAB1 augments the kinase activity of TAK1, indicating that TAB1 functions as an activator of TAK1 (5, 7). TAB2 functions as an adaptor linking TAK1 to TRAF6 by directly binding to both, thereby mediating TAK1 activation in the IL-1 signaling pathway (6,8).Several lines of evidence suggest that TAK1 is a key molecule in proinflammatory signaling pathways. Various proinflammatory cytokines and endotoxins activate the kinase activity of endogenous TAK1 (4, 9, 10). Overexpression of kinase-dead TAK1 inhibits IL-1-and TNF-induced activation of both JNK/p38 and NF-B (4, 10). The Drosophila homolog of TAK1 was recently identified as an essential molecule for host defense signaling in Drosophila (11). Furthermore, the TAK1 gene-silencing study using the small interfering RNA method defined that TAK1 is essential for both IL-1-and TNF-induced NF-B activation in mammalian cells (12). Therefore, it can be expected that inhibition of TAK1 activity may be effective in preventing inflammation and tissue destruction promoted by proinflammatory cytokines.In this study, we screened for compounds that can inhibit TAK1 kinase activity. This strategy resulted in the isolation of one natural compound 5Z-7-oxozeaenol, a resorcylic lactone of fungal ori...

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Section: Resultsmentioning

confidence: 99%

A Resorcylic Acid Lactone, 5Z-7-Oxozeaenol, Prevents Inflammation by Inhibiting the Catalytic Activity of TAK1 MAPK Kinase Kinase

Ninomiya‐Tsuji

Kajino

Ono³

et al. 2003

Journal of Biological Chemistry

391

348

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“…The MEK inhibitor Ro 09-2210 has been less well-characterized in terms of its specificity profile or antiinflammatory potential, but it has also been shown to inhibit LPS-induced TNF production in monocytes (49) and the proliferation and activation of T cells (50). Array BioPharma (Boulder, CO) is also developing potent and selective MEK inhibitors (16) and has reported significant efficacy data in animal models of inflammation and arthritis (51), further supporting the pivotal role of this kinase in inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms

Thiel

Schaefer²,

Lesch

et al. 2007

Arthritis & Rheumatism

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Objective. To evaluate the role of the MEK/ERK MAP kinase pathway in murine collagen-induced arthritis (CIA) using the selective MEK inhibitor PD184352. We examined the effects of the inhibitor in cytokine-stimulated synovial fibroblasts and in cytokine-induced arthritis in rabbits to investigate its antiinflammatory mechanisms.Methods. Murine CIA was used to assess the effects of the selective MEK inhibitor on paw edema, clinical scores, weight loss, histopathologic features, and joint levels of p-ERK. Western blotting and immunohistochemistry techniques were used to assess p-ERK in human and rabbit synovial fibroblasts and synovial tissue from rheumatoid arthritis (RA) patients. Interleukin-1␣ (IL-1␣)-stimulated stromelysin production in rabbit synovial fibroblasts was assessed by enzyme-linked immunosorbent assay. A rabbit IL-1␣-induced arthritis model was used to assess the effects of the inhibitor on IL-1␣-induced MEK activity, stromelysin production, and cartilage degradation.Results. In the CIA model, PD184352 inhibited paw edema and clinical arthritis scores in a dosedependent manner. Disease-induced weight loss and histopathologic changes were also significantly improved by treatment. Inhibition of disease-induced p-ERK levels in the joints was seen with the inhibitor. Levels of p-ERK in the synovium were higher in RA patients than in normal individuals. PD184352 reduced IL-1␣-induced p-ERK levels in human RA synovial fibroblasts. The production of p-ERK and stromelysin was also inhibited in IL-1␣-stimulated rabbit synovial fibroblasts. We observed IL-1␣-induced p-ERK in the synovial lining, subsynovial vasculature, and articular chondrocytes. IL-1␣-induced stromelysin production and proteoglycan loss from the articular cartilage were reduced by PD184352.Conclusion. These data demonstrate the inhibition of murine CIA by PD184352, support the hypothesis that antiinflammatory activity contributes to the mechanism of action of the inhibitor, and suggest that a selective inhibitor may effectively treat RA and other inflammatory disorders.

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“…Later on, other studies showed that overexpression of interfering mutants of MEK1 (Cowley et al, 1994;Seger et al, 1994), incubation with ERK2 antisense oligonucleotide (Sale et al, 1995) or expression of active MAP kinase phosphatase 1 (MKP-1/DUSP1) (Sun et al, 1994;Brondello et al, 1995) inhibits the induction of DNA synthesis by serum and activated Ras. Similarly, treatment with synthetic MEK1/2 inhibitors, which prevents activation of ERK1/ERK2, was reported to inhibit the proliferation of various cell types, including fibroblasts, T lymphocytes, smooth muscle cells, hepatocytes and epithelial cell lines (Dudley et al, 1995;Seufferlein et al, 1996;Karpova et al, 1997;DeSilva et al, 1998;Williams et al, 1998;SeboltLeopold et al, 1999;Talarmin et al, 1999). Conversely, expression of constitutively active forms of MEK1 (Brunet et al, 1994;Cowley et al, 1994;Seger et al, 1994) relaxes growth factor dependency and enhances the rate of cell proliferation.…”

Section: Sustained Activation Of the Erk1/2 Map Kinase Pathway Is Necmentioning

confidence: 99%

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

2007

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The Ras-dependent extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase pathway plays a central role in cell proliferation control. In normal cells, sustained activation of ERK1/ERK2 is necessary for G1-to S-phase progression and is associated with induction of positive regulators of the cell cycle and inactivation of antiproliferative genes. In cells expressing activated Ras or Raf mutants, hyperactivation of the ERK1/2 pathway elicits cell cycle arrest by inducing the accumulation of cyclin-dependent kinase inhibitors. In this review, we discuss the mechanisms by which activated ERK1/ERK2 regulate growth and cell cycle progression of mammalian somatic cells. We also highlight the findings obtained from gene disruption studies.

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Ro 09-2210 Exhibits Potent Anti-proliferative Effects on Activated T Cells by Selectively Blocking MKK Activity

Cited by 56 publications

References 50 publications

A Resorcylic Acid Lactone, 5Z-7-Oxozeaenol, Prevents Inflammation by Inhibiting the Catalytic Activity of TAK1 MAPK Kinase Kinase

A Resorcylic Acid Lactone, 5Z-7-Oxozeaenol, Prevents Inflammation by Inhibiting the Catalytic Activity of TAK1 MAPK Kinase Kinase

Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

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