PubMed · 8798202
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J A Irwin, K F Tipton. 1996. Affinity precipitation methods.. https://doi.org/10.1385/0-89603-336-8%3A217
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The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.
Small-molecule kinase inhibitors represent a major group of cancer therapeutics, but tumor responses are often incomplete. To identify pathways that modulate kinase inhibitor response, we conducted a genome-wide knockout (KO) screen in glioblastoma cells treated with the pan-ErbB inhibitor neratinib. Loss of general control nonderepressible 2 (GCN2) kinase rendered cells resistant to neratinib, whereas depletion of the GADD34 phosphatase increased neratinib sensitivity. Loss of GCN2 conferred neratinib resistance by preventing binding and activation of GCN2 by neratinib. Several other Food and Drug Administration (FDA)-approved inhibitors, such erlotinib and sunitinib, also bound and activated GCN2. Our results highlight the utility of genome-wide functional screens to uncover novel mechanisms of drug action and document the role of the integrated stress response (ISR) in modulating the response to inhibitors of oncogenic kinases.
1. Effects of oestrogen on the current evoked by ATP and benzoylbenzoyl ATP (BzATP) in CV-1 monkey kidney cells transformed by SV 40 (COS cells) expressing the human P2X7 (hP2X7) purinoceptor were studied using standard patch-clamp techniques. 2. 17beta-Oestradiol rapidly and reversibly inhibited the whole-cell hP2X7 receptor cation current. This inhibitory action resulted in a rightward shift of the dose-response curve to ATP and BzATP in the presence of physiological as well as low divalent cation concentrations. 3. The inhibitory effect of 17beta-oestradiol on the BzATP- or ATP-induced cation current was concentration dependent. The half-maximal inhibition was obtained with 3 microM 17beta-oestradiol. Progesterone and 17alpha-oestradiol had almost no effect on the hP2X7 receptor cation current. 4. The inhibition of the hP2X7 receptor cation current by 17beta-oestradiol did not depend on the membrane potential. 17beta-Oestradiol added to the extracellular side of outside-out patches inhibited BzATP-activated single-channel currents. 5. Activation of the hP2X7 receptor in both COS and U937 (human macrophage) cells did not induce the formation of large non-specific pores. 6. Since COS cells do not express endogenous nuclear oestrogen receptor, this study shows that, at pharmacological concentrations, 17beta-oestradiol inhibited the hP2X7 receptor cation channel in a non-genomic manner.