Signal Transduction through MAP Kinase Cascades

Lewis, Timothy S.; Shapiro, Paul; Ahn, Natalie G.

doi:10.1016/s0065-230x(08)60765-4

Cited by 1,630 publications

(1,248 citation statements)

References 760 publications

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“…26 We found that IL-13 treatment resulted in activation of ERK, which is known to be an important key players of MAPK pathway. 27 Further, we observed that AP-1, ERK1/2 activation occurred only in IL-13Ra2-transfected OVCAR-3 cells or naturally IL-13Ra2 overexpressing IGROV-1 cells by IL-13 stimulation, but not in control OVCAR-3 cells or IGROV-1 cells with knockdown of IL13Ra2. Since IL-4Ra and IL-13Ra1 are expressed in the ovarian carcinoma cells, we also investigated possible activation of IRS-PI3K-AKT and STAT6 pathway after IL-13 stimulation of ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 62%

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

Fujisawa

Joshi

Puri

2011

Intl Journal of Cancer

127

112

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Previously, we have demonstrated that a variety of human cancers including the ovarian cancer express IL-13Ra2, a high affinity receptor for IL-13. Herein, we have examined if IL-13 regulates invasion and metastasis of ovarian cancer through IL-13Ra2 in vitro and in vivo in animal models of human ovarian cancer. We tested cell invasion and protease activity in IL-13Ra2-overexpressing and IL-13Ra2-negative ovarian tumor cell lines. IL-13 treatment significantly augmented both cell invasion and enzyme activities in only IL-13Ra2-positive cells but not in IL-13Ra2-negative cells in vitro. Mechanistically, IL-13 enhanced ERK1/2, AP-1 and MMP activities only in IL-13Ra2-positive cells but not in IL-13Ra2-negative cells. In contrast, other signaling pathways such as IRS1/2, PI3K and AKT do not seem to be involved in IL-13 induced signaling in ovarian cancer cell lines. Highly specific inhibitors for MMP and AP-1 efficiently inhibited both invasion and protease activities without impacting the basal level invasion and protease activities in vitro. In orthotopic animal model of human ovarian cancer, IL-13Ra2-positive tumors metastasized to lymph nodes and peritoneum earlier than IL-13Ra2-negative tumors. Interestingly, the IL-13Ra2-positive tumor bearing mice died earlier than mice with IL-13Ra2-negative tumor. Intraperitoneal injection of IL-13 further shortened survival of IL-13Ra2-positive tumor bearing mice compared to IL-13Ra2-negative tumor mice. IL-13Ra2-positive tumors and lymph node metastasis expressed higher levels of MMPs and higher ERK1/2 activation compared to IL-13Ra2-negative tumors. Taken together, IL-13Ra2 is involved in cancer metastasis through activation of ERK/AP-1 and that targeting IL-13Ra2 might not only directly kill primary tumors but also prevent cancer metastasis.Ovarian cancer is the fifth major cause of cancer related deaths in women. It is estimated that 21,880 women will be diagnosed and 13,850 will die of ovarian cancer in 2010. 1 Severity of the disease is determined by staging, which is based on the distance and extent of cancer spread within the pelvic and peritoneal cavity. The 5-year survival rate of ovarian cancer patients is related to the stage of the disease. 2 Therefore, novel and effective anticancer therapies are needed to prevent cancer cell spread. We have previously reported that IL13Ra2 is a biomarker of disease in ovarian cancer and targeting of this receptor with specific immunotoxin decreases tumor burden and extends survival of animals. 3 Despite its overexpression in a variety of human tumors and its characterization as a potent target for receptor directed anticancer therapy, 4-7 the biology of this receptor is highly complex and not understood completely. IL-13Ra2 is one of two receptor subunits of IL-13R complex. Another key-player of the receptor complex is IL-13Ra1, which forms a productive complex with IL-4Ra upon binding to IL-13 and mediates signal transduction. On the other hand, IL13Ra2 does not seem to require IL-4Ra and by itself binds IL-13 with high af...

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Section: Discussionmentioning

confidence: 62%

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

Fujisawa

Joshi

Puri

2011

Intl Journal of Cancer

127

112

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“…The MAPK pathway consists of three major members: c-Jun-NH 2 -terminal kinase (JNK), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 [24]. Their specific inhibitors including: SP600125 (10 -5 M, inhibitor of JNK) [25], PD98059 and U0126 (10 -5 M, inhibitors of ERK1/2) [26,27] and SB203580 (10 -5 M, inhibitor of p38) [28] were employed to examine the involvement of different MAPK subtypes.…”

Section: Intracellular Signal Inhibitions and Drugsmentioning

confidence: 99%

Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms

Zhang

Edvinsson

et al. 2008

Atherosclerosis

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“…1 Activation of the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) is required for mitogenesis, and mediates neoplastic transformation signals from a wide variety of oncogenic stimuli. 1 Accumulating evidence indicates that the extent and intensity of MAPK activation, as well as the cellular context, influence the biological outcomes. 2 Indeed, besides the mitogenic response, MAPK can promote growth arrest, differentiation, replicative senescence, apoptosis, or resistance to radio-and chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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Stimulation of the Ras/MAPK cascade can either activate p53 and promote replicative senescence and apoptosis, or degrade p53 and promote cell survival. Here we show that p53 can directly counteract the Ras/MAPK signaling by inactivating ERK2/MAPK. This inactivation is due to a caspase cleavage of the ERK2 protein and contributes to p53-mediated growth arrest. We found that in Ras-transformed cells, growth arrest induced by p53, but not p21 Waf1 , is associated with a strong reduction in ERK2 activity, phosphorylation, and protein half-life, and with the appearance of caspase activity. Likewise, DNA damage-induced cell cycle arrest correlates with p53-dependent ERK2 downregulation and caspase activation. Furthermore, caspase inhibitors or expression of a caspase-resistant ERK2 mutant interfere with ERK2 cleavage and restore proliferation in the presence of p53 activation, indicating that caspase-mediated ERK2 degradation contributes to p53-induced growth arrest. These findings strongly point to ERK2 as a novel p53 target in growth suppression.

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Signal Transduction through MAP Kinase Cascades

Cited by 1,630 publications

References 760 publications

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

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