13 research outputs found
Effect of Dietary Potassium Supplementation to Sows During Lactation on Electrolyte Status of the Sows and Piglets1
Signal transducer and activator of transcription 1 (Stat1) maintains basal mRNA expression of pro-survival stat3-target genes in glioma C6 cells
Medicinal chemistry updates on quinoline- and endoperoxide-based hybrids with potent antimalarial activity
Glucose Activates ChREBP by Increasing Its Rate of Nuclear Entry and Relieving Repression of Its Transcriptional Activity*S⃞
Carbohydrate response element-binding protein (ChREBP) is a
glucose-responsive transcription factor that activates genes involved in
de novo lipogenesis in mammals. The current model for glucose
activation of ChREBP proposes that increased glucose metabolism triggers a
cytoplasmic to nuclear translocation of ChREBP that is critical for
activation. However, we find that ChREBP actively shuttles between the
cytoplasm and nucleus in both low and high glucose in the glucose-sensitive
β cell-derived line, 832/13. Glucose stimulates a 3-fold increase in the
rate of ChREBP nuclear entry, but trapping ChREBP in the nucleus by
mutagenesis or with a nuclear export inhibitor does not lead to constitutive
activation. In fact, mutational studies targeting the nuclear export signal of
ChREBP also identified a distinct function essential for glucose-dependent
transcriptional activation. From this, we conclude that an additional event
independent of nuclear translocation is required for activation. The
N-terminal segment of ChREBP (amino acids 1-298) has previously been shown to
repress activity under basal conditions. This segment has five highly
conserved regions, Mondo conserved regions 1-5 (MCR1 to -5). Based on
activating mutations in MCR2 and MCR5, we propose that these two regions act
coordinately to repress ChREBP in low glucose. In addition, other mutations in
MCR2 and mutations in MCR3 were found to prevent glucose activation. Hence, we
conclude that both relief of repression and adoption of an activating form are
required for ChREBP activation
Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3*
Excessive neuroinflammation contributes to many neurological disorders and
is poorly controlled therapeutically. The signal transducer and activator of
transcription (STAT) family of transcription factors has a central role in
inflammatory reactions, being stimulated by multiple cytokines and interferons
and regulating the expression of many proteins involved in inflammation. We
found that STAT3 activation is highly dependent on glycogen synthase kinase-3
(GSK3). Inhibitors of GSK3 greatly reduced (>75%) the activating STAT3
tyrosine phosphorylation in mouse primary astrocytes, microglia, and
macrophage-derived RAW264.7 cells induced by interferon-γ (IFNγ),
IFNα, interleukin-6, or insulin. GSK3 inhibitors blocked STAT3 DNA
binding activity and the expression of STAT3-induced GFAP and Bcl-3. GSK3
dependence was selective for activation of STAT3 and STAT5, whereas STAT1 and
STAT6 activation were GSK3-independent. Knockdown of the two GSK3 isoforms
showed STAT3 and STAT5 activation were dependent on GSK3β, but not
GSK3α. The regulatory mechanism involved GSK3β binding STAT3 and
promoting its association with the IFNγ receptor-associated
intracellular signaling complex responsible for activating STAT3. Furthermore,
GSK3β associated with the IFNγ receptor and was activated by
stimulation with IFNγ. Thus, inhibitors of GSK3 reduce the activation of
STAT3 and STAT5, providing a mechanism to differentially regulate STATs to
modulate the inflammatory response