http://nova.newcastle.edu.au/vital/access/services/Feed ${session.getAttribute("locale")} 5 http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:5522 Rationale: Although epidemiological studies have linked asthma susceptibility and severity to polymorphisms in human glutathione transferase Pi (GSTP) 1, there is no direct evidence for a functional involvement of GSTP1 in processes that are pathognomic of asthma. Objectives: To examine the role of GSTP1 in modulating the development of allergic airways disease. Methods: Allergic airways disease was induced in wild-type (WT) and Gstp-null mice employing both acute and chronic models. Eosinophilia, goblet cells, and remodeling were quantified by histological assessment; respiratory function was determined using invasive methods. ELISA was used to evaluate Th2 cytokines, eotaxin, and phospho-c-Jun. Gstp1/2 expression was quantified by reverse transcriptase–polymerase chain reaction. Measurements and Main Results: Compared with allergic WT mice, eosinophilia, goblet cell hyperplasia, airway remodeling, lung resistance, and IL-5 were enhanced in allergic Gstp-null mice. However, the protective efficacy of GSTP1 was mouse-strain dependent, and associated with inherent variation in expression of Gstp1. Although elevated levels of phospho-c-Jun were detected in Gstp-null mice, treatment of WT mice with a GSTP/c-Jun N-terminal kinase (JNK) inhibitory peptide enhanced phospho-c-Jun and significantly attenuated allergic responses. Conclusions: GSTP1 attenuates the severity of allergic airways disease. However, the efficacy of GSTP1 correlated with mouse strain-dependent variation in Gstp1 expression. Although GSTP1 attenuated c-Jun phosphorylation, treatment with a GSTP/JNK inhibitory peptide revealed an inverse relationship between c-Jun phosphorylation and allergic responses, indicating that the mechanism by which GSTP attenuates allergic responses is not dependent on the JNK/c-Jun axis. Our data, together with epidemiological evidence, suggest variation in expression and/or function of this protein is an important determinant in asthma pathophysiology. 2010-04-27T04:43:21.965Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:5394 Our previous studies revealed that Docetaxelinduced apoptosis of melanoma cells is entirely dependent on activation of the JNK signalling pathway. Here, we show that Docetaxel-induced apoptosis is mediated by induction of ER stress. This was shown by Docetaxelinduced activation of proteins involved in ER stress signalling namely GRP78, ATF6, IRE1α, and PERK/eIF2α. Knockdown of IRE1α by siRNA markedly inhibited Docetaxel-induced JNK activation and downstream targets of JNK indicating that activation of IRE1α was upstream of activation of the JNK. Co-immunoprecipitation experiments showed that activation of JNK is due to activation of ASK1 through formation of an IRE1α-TRAF2-ASK1 complex. ER stress mediated activation of the JNK pathway is downstream of activation of PKCδ in that downregulation of PKCδ expression using specific PKCδ siRNA significantly inhibited Docetaxel-induced activation of IRE1α and the JNK pathway. These findings provide new insights to understand the mode of action of taxanes in treatment of human melanoma. 2010-04-27T04:37:50.202Z ]]>