p38 MAP Kinase's Emerging Role as a Tumor Suppressor

Bulavin, Dmitry V.; Fornace, Albert J.

doi:10.1016/s0065-230x(04)92005-2

Cited by 263 publications

(212 citation statements)

References 98 publications

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“…Activation of p38 signaling mediates transcriptional activation of MMP-2 and MMP-9 (36,37), but the role of p38 in tumor metastasis is controversial (for reviews, refs. 19,21,38]. Although the activation of p38 Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Deacetylated GM3 Promotes uPAR-Associated Membrane Molecular Complex to Activate p38 MAPK in Metastatic Melanoma

Qiu

Bach

Gatla

et al. 2013

Molecular Cancer Research

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GM3, the simplest ganglioside, regulates cell proliferation, migration, and invasion by influencing cell signaling at the membrane level. Although the classic N-acetylated form of GM3 (NeuAcLacCer) is commonly expressed and has been well studied, deacetylated GM3 (NeuNH 2 LacCer, d-GM3) has been poorly investigated, despite its presence in metastatic tumors but not in noninvasive melanomas or benign nevi. We have recently found that d-GM3 stimulates cell migration and invasion by activating urokinase plasminogen activator receptor (uPAR) signaling to augment matrix metalloproteinase-2 (MMP-2) function. However, the mechanisms by which d-GM3/ uPAR increase MMP-2 expression and activation are not clear. By modifying the expression of d-GM3 genetically and biochemically, we found that decreasing d-GM3 expression inhibits, whereas overexpressing d-GM3 stimulates, p38 mitogen-activated protein kinase (MAPK) activity to influence MMP-2 expression and activation. p38 MAPK (p38) activation requires the formation of a membrane complex that contains uPAR, caveolin-1, and integrin a5b1 in membrane lipid rafts. In addition, knocking down or inhibiting focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), or Src kinase significantly reduces d-GM3-induced p38 phosphorylation and activation. Taken together, these results suggest that d-GM3 enhances the metastatic phenotype by activating p38 signaling through uPAR/integrin signaling with FAK, PI3K, and Src kinase as intermediates. Elucidation of the mechanisms by which d-GM3, a newly discovered, potential biomarker of metastatic melanomas, promotes cell metastasis will help us to understand the function of d-GM3 in metastatic melanomas and may lead to novel GM3-based cancer therapies. Mol Cancer Res; 11(6); 665-75. Ó2013 AACR. IntroductionAlthough recent therapeutic progress for metastatic melanomas has significantly improved, including the more recent availability of small-molecule inhibitors targeting BRAF mutation or both BRAF mutation and MEK, or anti-CTLA4 antibody, survival is minimally prolonged and mortality rate of metastatic melanomas remains high (1-3). It is of utmost importance to discover specific molecular biomarkers that can distinguish melanomas with metastatic propensity from more indolent ones, which will improve prognostication, allow for earlier and more efficacious treatments, and provide additional targets for novel therapy.

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Section: Discussionmentioning

confidence: 99%

Deacetylated GM3 Promotes uPAR-Associated Membrane Molecular Complex to Activate p38 MAPK in Metastatic Melanoma

Qiu

Bach

Gatla

et al. 2013

Molecular Cancer Research

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“…In other cell systems, delayed activation of the p38 MAP kinase pathway also has a negative impact on cell proliferation by inducing apoptosis (Daly et al, 1999;Takekawa et al, 2002;Bulavin and Fornace, 2004;Naito et al, 2004). Treatment of BT474 and SKBr3 cells with anti-HER2 antibodies for 72 h does not induce significant apoptosis (Le et al, 2003(Le et al, , 2005a.…”

Section: Discussionmentioning

confidence: 99%

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin s ) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro-and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

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“…Actually, Raf/MEK/ ERK and MKK3/6-p38 represent two independent mitogen-activated protein kinase (MAPK) pathways. Whereas the Raf/MEK/ERK cascade transduces proliferative signals, the MKK3/6-p38 cascade is a major mediator of stress responses that usually leads to growth arrest or apoptosis (Kim et al, 2002;Xiu et al, 2003;Bulavin and Fornace, 2004;Yee et al, 2004). It was reported that the MKK3/6-p38 cascade functions as downstream of the Raf/MEK/ERK cascade to mediate senescence.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Wang

Liu

et al. 2010

Oncogene

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Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras-and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16 INK4A cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16 INK4A gene contains an HBP1-binding site at position À426 to À433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16 INK4A gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16 INK4A gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16 INK4A to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.

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p38 MAP Kinase's Emerging Role as a Tumor Suppressor

Cited by 263 publications

References 98 publications

Deacetylated GM3 Promotes uPAR-Associated Membrane Molecular Complex to Activate p38 MAPK in Metastatic Melanoma

Deacetylated GM3 Promotes uPAR-Associated Membrane Molecular Complex to Activate p38 MAPK in Metastatic Melanoma

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

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