Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

GRIM-19 represses STAT3 transcriptional activity but has no effect on other STAT proteins
and is therefore a specific negative regulator of STAT3. GRIM-19 was shown to suppress
growth in Src transformed cells which have constitutive STAT3 activity, inhibit cellular
transformation induced by constitutively active STAT3 and substantially reduce tumor
volume in xenografts from STAT3 overexpressing cells (Lufei et al., 2003, Kalakonda et al.,
2007). Therefore GRIM-19 represents a novel inhibitor of STAT3 activity and may have
important roles in limiting the oncogenic potential of STAT3 in cancer.
1.3.10 Non-Transcriptional Regulation of Gene Expression by STATs
Recently RNAi screens in Drosophila have found interactions between the JAK/STAT
pathway and chromatin regulators. Shi et al. conducted a genetic screen for modifiers of the
oncogenic allele of the Drosophila JAK homolog Hop known as tumorous lethal ( -1 ). They
identified several chromatin modifying genes such as the non-histone chromosomal protein
heterochromatin 1 (HP-1), the histone methyl transferase Su(var)3-9 and the histone
deacetylase Rpd3 and found that crossing flies deficient in either of these genes with -1 flies
resulted in increased numbers of melanoic tumors (Shi et al., 2006). Moreover, these genes
are essential components of heterochromatin and over-activity of Hop/JAK was found to
block heterochromatin-mediated silencing of genes which are not normally regulated by the
JAK/STAT pathway (Shi et al., 2006). Increasing heterochromatic gene silence via a HP-1
transgenic completely abolished -1
tumorigenicity, suggesting that heterochromatic gene
silencing is necessary for constitutive JAK mediated tumorigenesis. The Drosophila STAT
homolog STAT92E was found to bind to HP-1 only when STAT92E was unphosphorylated,
this association was present in the nucleus where it was responsible for stabalised HP-1
localisation and histone H3 methylation (Shi et al., 2008). STAT92E phosphorylation led to
reduced heterchomatin localization, dissociation of HP-1 and heterochromatin destabilization
suggesting that STAT phosphorylation may therefore regulate access to chromatin.
Chromatin remodeling through the JAK/STAT pathway has also been shown in human cells.
Phosphorylation of STAT1 was found to be essential for remodeling of the major
histocompatibility complex (MHC) locus, where following IFN- stimulation the chromatin
carrying the entire locus loops out from chromosome 6 (Christova et al., 2007). Binding of
STAT1 to the MHC gene engaged recruitment of the chromatin remodeling enzyme BRG1
48