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Jun N-terminal Protein Kinase (jun + n-terminal_protein_kinase)
Selected AbstractsRoles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras -transformed human breast epithelial cellsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2003Hye-Jung Kang Abstract Efforts have been made to develop a chemoprevention strategy that selectively triggers apoptosis in malignant cancer cells. Previous studies showed that capsaicin, the major pungent ingredient of red pepper, had differential effect between normal and transformed cells. As an approach to unveil the molecular mechanism by which capsaicin selectively induces apoptosis in transformed cells, we investigated the effect of capsaicin in nontransformed and ras -transformed cells of a common origin: parental (MCF10A) and H- ras -transformed (H- ras MCF10A) human breast epithelial cells. Here, we show that capsaicin selectively induces apoptosis in H- ras -transformed cells but not in their normal cell counterparts. The capsaicin-induced apoptosis, which is dependent on ras transformation, involves the activity of DEVDase (caspase-3 like). In H - ras MCF10A cells, capsaicin treatment markedly activated c-Jun N-terminal protein kinase (JNK)-1 and p38 matigen-activated protein kinase (MAPK) while it deactivated extracellular signal-regulated protein kinases (ERKs). The use of kinase inhibitors and overexpression of dominant-negative forms of MAPKs demonstrated a role of JNK-1 and p38, but not that of ERKs, in apoptosis induced by capsaicin in H- ras -transformed MCF10A cells. Based on the present study, we propose that capsaicin selectively induces apoptosis through modulation of ras -downstream signaling molecules in ras -activated MCF10A cells. Taken in conjunction with the fact that uncontrolled ras activation is probably the most common genetic defect in human cancer cells, our finding may be critical to the chemopreventive potential of capsaicin and for developing a strategy to induce tumor cell-specific apoptosis. © 2002 Wiley-Liss, Inc. [source] Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells,MOLECULAR CARCINOGENESIS, Issue 1 2010Mallikarjuna Gu Abstract Constitutively active mitogenic and prosurvival signaling cascades due to aberrant expression and interaction of growth factors and their receptors are well documented in human prostate cancer (PCa). Epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) are potent mitogens that regulate proliferation and survival of PCa cells via autocrine and paracrine loops involving both mitogen-activated protein kinase (MAPK)- and Akt-mediated signaling. Accordingly, here we assessed the effect of inositol hexaphosphate (IP6) on constitutive and ligand (EGF and IGF-1)-induced biological responses and associated signaling cascades in advanced and androgen-independent human PCa PC-3 cells. Treatment of PC-3 cells with 2,mM IP6 strongly inhibited both growth and proliferation and decreased cell viability; similar effects were also observed in other human PCa DU145 and LNCaP cells. IP6 also caused a strong apoptotic death of PC-3 cells together with caspase 3 and PARP cleavage. Mechanistic studies showed that biological effects of IP6 were associated with inhibition of both constitutive and ligand-induced Akt phosphorylation together with a decrease in total Akt levels, but a differential inhibitory effect on MAPKs extra cellular signal-regulated kinase 1/2 (ERK1/2), c- Jun N-terminal protein kinase (JNK1/2), and p38 under constitutive and ligand-activated conditions. Under similar condition, IP6 also inhibited AP-1 DNA-binding activity and decreased nuclear levels of both phospho and total c-Fos and c- Jun. Together, these findings for the first time establish IP6 efficacy in inhibiting aberrant EGF receptor (EGFR) or IGF-1 receptor (IGF-1R) pathway-mediated sustained growth promoting and survival signaling cascades in advanced and androgen-independent human PCa PC-3 cells, which might have translational implications in advanced human PCa control and management. © 2009 Wiley-Liss, Inc. [source] Activation of NF-,B and IL-8 by Yersinia enterocolitica invasin protein is conferred by engagement of Rac1 and MAP kinase cascadesCELLULAR MICROBIOLOGY, Issue 12 2003Guntram A. Grassl Summary Yersinia enterocolitica triggers activation of the nuclear factor (NF)-,B and production of the proinflammatory chemokine interleukin (IL)-8 in intestinal epithelial cells. This activation is due to adhesion of the bacteria via their outer membrane protein invasin to the host cells. Using Clostridium difficile toxins that specifically inactivate small GTPases, and transfection of inhibitory proteins of the Rho-GTPases, we demonstrate that Rac1, but not Cdc42 or Rho, is required for activation of NF-,B by invasin. Invasin activated the mitogen activated protein kinases (MAPK) p38 and c-Jun N-terminal protein kinase (JNK) but not extracellular signal regulated kinase (ERK). The functional relevance of these pathways for invasin-mediated IL-8 expression was assessed by protein kinase inhibitors and dominant-negative kinase mutants. While NF-,B and JNK contribute to IL-8 transcription, p38 MAPK also acts through stabilization of IL-8 mRNA, as confirmed by quantitative RT-PCR and electrophoretic mobility shift assays. Transfection experiments with I-,B kinase (IKK)1 and IKK2 mutants indicate that the release of NF-,B from its cytoplasmic inhibitor I-,B and its translocation into the nucleus is mediated by these kinases. Our data identify Rac1 as a key intermediate in invasin-triggered IL-8 synthesis and demonstrate that maximum IL-8 induction involves several MAP kinase cascades. [source] p38, MAP kinase protects rat mesangial cells from TNF-,-induced apoptosisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2001Yan-Lin Guo Abstract p38 MAP kinases (p38) and c-Jun N-terminal protein kinases (JNK) have been associated with TNF-,-induced apoptosis. However, recent studies indicate that an early but brief activation of JNK and/or p38 may actually protect some cells from TNF-,-induced apoptosis. Whether the activation of JNK and p38 provides a pro- or anti-apoptotic signal for TNF-, has been controversial. In this study, we investigated the role of p38 in the regulation of TNF-, cytotoxicity in rat mesangial cells. Treatment of the cells with TNF-, alone had little effect on their viability, but they became very sensitive to apoptosis when treated with TNF-, in the presence of the p38 inhibitor SB 203580. These results suggested that the p38 pathway is critical for mesangial cells to survive the toxic effect of TNF-,. Using adenovirus-mediated gene transfer technique, we further demonstrated that p38,, but not p38,, is essential to protect the cells from TNF-, toxicity. It has been speculated that there is a synergetic interaction between the p38 and the nuclear factor-,B (NF-,B) pathways in protecting certain cells from apoptosis. However, expression of neither p38, nor its dominant negative mutant in mesangial cells interfered with TNF-,-induced translocation of NF-,B, the initial step of NF-,B activation. While it is unclear whether p38, regulates NF-,B transcription activity at other steps, it is apparent that p38, does not affect TNF-,-induced NF-,B activation at the stage of nuclear translocation. J. Cell. Biochem. 82: 556,565, 2001. © 2001 Wiley-Liss, Inc. [source] Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2009Liang Zhang Rituximab (RTX), a chimeric anti-CD20 antibody, is associated with direct induction of apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) with clinical efficacy in mantle cell lymphoma (MCL). Lenalidomide (LEN), a novel immunomodulatory agent, sensitizes tumor cells and enhances ADCC. Our study attempted to elucidate the mechanism of LEN-enhanced RTX-mediated cytotoxicity of MCL cells. We found that LEN and RTX induced growth inhibition of both cultured and fresh primary MCL cells. LEN enhanced RTX-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Meanwhile, LEN activated NK cells and increased CD16 expression on CD56lowCD16+ NK cells. Whole PBMCs but not NK cell-depleted PBMCs treated with LEN augmented 30% of RTX-dependent cytotoxicity. Daily treatment with LEN increased NK cells by 10-folds in SCID mice, and combination of LEN and RTX decreased tumor burden and prolonged survival of MCL-bearing SCID mice. Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing apoptosis and RTX-dependent NK cell-mediated cytotoxicity and may be an optimal combination in the clinical trial of relapsed or refractory MCL. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||