Secreted GH can exist in both free and bound states by the GHBP (the secondary domain of the GH receptor)[19]. Also, activation of liver GH receptor, promotes IGF-I synthesis which, in turn, is released to the circulation and can be found in its free form but mainly bound to IGFBPs (overall IGFBP-3, which binds 90% of circulating IGF-I)[23].
Reactive Oxygen Species (ROS) is a phrase used to describe a number of reactive molecules and free radicals derived from molecular oxygen. The production of oxygen based radicals is the bane to all aerobic species. These molecules, produced as byproducts during the mitochondrial electron transport of aerobic respiration or by oxidoreductase enzymes and metal catalyzed oxidation, have the potential to cause a number of deleterious events. It was originally thought that only phagocytic cells were responsible for ROS production as their part in host cell defense mechanisms. Recent work has demonstrated that ROS have a role in cell signaling, including; apoptosis; gene expression; and the activation of cell signaling cascades [1]. It should be noted that ROS can serve as both intra- and intercellular messengers.
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The fourth MAP kinase of interest in this context is ERK5 [2]. Relatively, it is of large molecular size [162], with its activation being carried out by the MAPKK MEK5 [163], which is itself activated by MEKK2 or 3 [164]. While distantly related to, and sharing its mechanism of molecular action with, ERK1/2, gene knockout studies in mice show ERK5 to have non-redundant functions in heart development [165], vasculogenesis and angiogenesis [166] and endothelial cell survival [166]. Cell culture based experiments have pointed to ERK5 functioning at a molecular level in mitosis [167] and cell survival [168]. ERK5 is activated by growth factors [169], integrin engagement [170] and cell stress [167], and its important molecular targets would seem to include the induction of transcription of components of the transcription factor AP-1 (cJun [171] and Fos [172]) and activation of transcription factors of the myocyte enhancer family group (for example, MEF2C, a well characterised target [173]), and cMyc [174]. Serum and glucocorticod kinase is an interesting target kinase of ERK5 [175]; it may mediate cell survival influences of ERK5 to cellular stress [176]. Interestingly, in 20% of a human breast tumour set analysed, ERK5 levels were elevated and activated ERK5 (phospho-ERK5) was detected in many of the tumours. High levels of ERK5 were found to be an independent predictor of disease-free survival in this cohort and was associated with poor disease outcome [177]. Complementing these findings are, firstly, studies on ERK5 knockdown (using short hairpin RNA) in a human breast cancer cell line, which showed a sensitisation to the effects of ErbB 2 inhibitors [177]; secondly, studies in human breast cancer cell lines that associate constitutively active ERK5 with induced ErbB2, 3 and 4 activation [178]; and, thirdly, that such cells harbouring a dominant defective ERK5 show reduced proliferation rates, which may be due to failure to activate ErbB2 [178]. 2ff7e9595c
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