3 research outputs found
Tyrosine Phosphorylation of Mig6 Reduces Its Inhibition of the Epidermal Growth Factor Receptor
Under
physiological conditions, epidermal growth factor receptor
(EGFR) tyrosine kinase activity is tightly controlled through the
coordinated action of both positive and negative regulators. Aberrant
EGFR activation occurs frequently in many cancer types, and the endogenous
EGFR feedback inhibitor, Mig6/RALT, is more efficiently phosphorylated
by oncogenic EGFR variants. We have utilized expressed protein ligation
to generate semisynthetic Tyr394 phosphorylated and unphosphorylated
forms of the Mig6 protein and shown that phosphorylation of Mig6 reduces
its ability to inhibit purified, near full-length EGFR (tEGFR). We
also demonstrate that the kinetic parameters of tEGFR are similar
whether solubilized in detergent or reconstitutued in nanodisc bilayers.
These findings suggest a mechanism by which EGFR and its family members
evade negative regulation by Mig6 under pathological conditions
A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1
Lysine-specific
demethylase 1 (LSD1) is an epigenetic enzyme that
oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4
of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing.
This study describes the design and synthesis of analogues of a monoamine
oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties.
A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide
appendage was shown to be a potent LSD1 inhibitor <i>in vitro</i> and was selective versus monoamine oxidases A/B and the LSD1 homologue,
LSD2. Bizine was found to be effective at modulating bulk histone
methylation in cancer cells, and ChIP-seq experiments revealed a statistically
significant overlap in the H3K4 methylation pattern of genes affected
by bizine and those altered in LSD1–/– cells. Treatment
of two cancer cell lines, LNCaP and H460, with bizine conferred a
reduction in proliferation rate, and bizine showed additive to synergistic
effects on cell growth when used in combination with two out of five
HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress
were protected by the presence of bizine, suggesting potential applications
in neurodegenerative disease
A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1
Lysine-specific
demethylase 1 (LSD1) is an epigenetic enzyme that
oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4
of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing.
This study describes the design and synthesis of analogues of a monoamine
oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties.
A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide
appendage was shown to be a potent LSD1 inhibitor <i>in vitro</i> and was selective versus monoamine oxidases A/B and the LSD1 homologue,
LSD2. Bizine was found to be effective at modulating bulk histone
methylation in cancer cells, and ChIP-seq experiments revealed a statistically
significant overlap in the H3K4 methylation pattern of genes affected
by bizine and those altered in LSD1–/– cells. Treatment
of two cancer cell lines, LNCaP and H460, with bizine conferred a
reduction in proliferation rate, and bizine showed additive to synergistic
effects on cell growth when used in combination with two out of five
HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress
were protected by the presence of bizine, suggesting potential applications
in neurodegenerative disease