ABSTRACT
ING
proteins affect apoptosis, growth, and DNA repair by transducing stress
signals such as DNA damage, binding histones, and subsequently
regulating chromatin structure and p53 activity. p53 target genes,
including the p21 cyclin-dependent kinase inhibitor and Bax, an inducer
of apoptosis, are regulated by ING proteins. To identify additional
targets downstream of p33ING1 and p32ING2, cDNA
microarrays were performed on phenotypically normal human primary
fibroblasts. The 0.36% of genes affected by ING proteins in primary
fibroblasts were distinct from targets seen in established cells and
included the HSP70 heat shock gene, whose promoter was specifically
induced >10-fold. ING1-induced expression of HSP70 shifted
cells from survival to a death pathway in response to tumor necrosis
factor alpha (TNF-α), and p33ING1b protein showed
synergy with TNF-α in inducing apoptosis, which correlated with
reduced NF-κB-dependent transcription. These findings are
consistent with previous reports that HSP70 promotes
TNF-α-mediated apoptosis by binding I-κΒ kinase
gamma and impairing NF-κB survival signaling. Induction of
HSP70 required the amino terminus of ING1b but not the plant
homeodomain region that was recently identified as a histone binding
domain. Regulation of HSP70 gene expression by the ING tumor
suppressors provides a novel link between the INGs and the
stress-regulated NF-κB survival pathway important in hypoxia
and
angiogenesis.
Raf Kinase Inhibitor Protein (RKIP) Inhibits Tumor Necrosis Factor-α (TNF-α) Induced Adhesion Molecules Expression in Vascular Smooth Muscle Bells by Suppressing (Nuclear Transcription Factor-κB (NF-kappaB) Pathway
