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a range of external stimuli. With ligands transducing their signal using the MAPK
pathway to produce prominent phenotypic features crucial in tumour develop-
ment and dissemination, MKK1 (MAP2K1) has quite deservedly enjoyed attention
in respect of its relevance to the pathogenetic process. This has led to an extensive
study of MAPK mediation of cell proliferation, migration and neovascularisation.
MKK was described as a metastasis suppressor. Yoshida et  al. (1999) reported that
MKK4 (MAP2K4) behaved as metastasis suppressor gene in AT6.1 rat prostate can-
cer cells. AT6.1 cells carrying transfected MKK4 displayed greatly reduced meta-
static spread as compared with control cells in vivo , without affecting the growth of
the primary tumours. A more informative study is that of Stark et  al. (2005) who
found that in brain metastases of breast cancers, the suppressor genes KiSS1, KAI1,
BRMS and MKK4 expression was reduced to one-tenth of the level of the primary
tumours. This possibly suggests the component cells of the primary tumour with
downregulated expression might be predisposed to form the metastatic clones. It
is difficult to determine the relative importance of the individual genes that were
downregulated in metastatic deposits. Interestingly they found nm23 expression was
unaltered between primary tumours and brain metastases. In prostate cancer, MKK4
expression has shown an inverse relationship to Gleason score (Kim et al., 2001).
On the other hand, there are reports that MKK4 induces rather than suppresses
oncogenic changes. Experimentally enhanced expression of MKK4, in breast and
pancreatic cancer cell lines not expressing the gene, induced cell proliferation and
invasion, whilst inhibition of expression by siRNA in MKK4 expressing cell line
MDA-MB-231 decreased anchorage-independent growth and suppressed tumour
growth in vivo (Wang et al., 2004a).
The Inhibitory Effects of Anthrax Lethal Toxin on MKKs
The Anthrax lethal toxin (LeTx) is an inhibitor of MKKs. It specifically targets
many members of the MKK family and has been used in many studies relating to
tumour biology. LeTx is a binary or ternary complex of three proteins, namely the
protective antigen, the lethal factor and the oedema factor. Both the lethal factor
and the oedema factor are enzymes; the lethal factor is Zn 2+ -dependent MMP and
the oedema factor is adenylate cyclase. The protective antigen mediates the bind-
ing of the toxin to the cell and its translocation into the cells (Pannifer et al., 2001;
Thoren and Krantz, 2011; Young and Collier, 2007). LeTx binds at the cell surface
with specific receptors CMG2 (capillary morphogenesis gene 2) and TEM8 (tumour
endothelial marker 8). The protective antigen binds to the integrin-like extracellu-
lar domain of the receptors and promotes the internalisation of the toxin into the
cytoplasm. CMG2, TEM8 and integrin β1 contain the von Willebrand A (adhesive)
domain which is essential for the binding of the toxin to the receptor. TEM8 is dif-
ferentially expressed in normal and tumour associated vasculature and expression in
the latter might be related to tumour stage. It is upregulated during vasculogenesis
and formation of tumour vasculature and expressed copiously (St Croix et al., 2000;
Rmali et  al., 2005; Carson-Walter et  al., 2001; Bradley and Young, 2003). Three
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