PubMed · 7568248
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M J Müller. 1995. Hepatic fuel selection.. https://doi.org/10.1079/pns19950043
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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. Whole-cell recordings were made from rat nodose ganglion neurones in culture and from human embryonic kidney (HEK293) cells stably transfected to express P2X2, P2X3 or both receptor subunits. We examined the blocking actions of 2',3'-O-trinitrophenyl-ATP (TNP-ATP) on currents evoked by the agonists ATP and alpha, beta-methylene ATP. 2. In cells expressing only P2X2 or P2X3 receptor subunits, the inhibition by TNP-ATP was fitted by a single binding site model with half-maximal concentrations of about 3 microM and 3 nM, respectively. In cells expressing both P2X2 and P2X3 receptor subunits, currents showed little or no desensitization, thus excluding contributions from homomeric P2X3 receptors. When alpha,beta-methylene ATP was the agonist (activating heteromeric P2X2/3 receptors), the inhibition by TNP-ATP conformed to a single binding site (half-maximal concentration about 3 nM). When ATP (30 microM) was the agonist, activating both heteromeric P2X2/3 as well as homomeric P2X2 receptors, the inhibition curve was biphasic (half-maximal concentrations about 3 nM and 3 microM); the proportion of high affinity sites in all six cells tested was about 40 %. 3. In nodose ganglion neurones, the inhibition by TNP-ATP of currents evoked by ATP (30 microM) was also clearly biphasic. In this case, individual neurones showed more variability in the proportion of high and low affinity sites for TNP-ATP. 4. We conclude that more than one form of multimeric P2X receptor channels are functionally expressed on the cell bodies of individual nodose ganglion neurones. On the basis of sensitivity to TNP-ATP, and other properties, one of these may correspond to the homomeric P2X2 receptor and the other(s) to heteromeric P2X2/3 receptors.