PubMed · 11101825
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A J Vidal-Puig. 2000. Uncoupling expectations.. https://doi.org/10.1038/82489
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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.
A peripheral injection of glucose has been found to improve memory in rats, but the underlying mechanisms are unknown. One possible mechanism by which peripheral glucose might act on memory storage is by regulating ATP-sensitive potassium (K-ATP) channels. The present study investigated the effects of K-ATP channel modulators (minoxidil, a K-ATP channel opener and glibenclamide, a K-ATP channel closer) on memory enhancement induced by peripheral injection of glucose in an inhibitory avoidance task. Rats were trained in a one trial inhibitory avoidance task (50 Hz, 1 mA, 3 s footshock), and minoxidil (12.5,25 or 50 mg/kg) or glibenclamide (2.5,5,10 or 20 mg/kg) was injected interaperitoneally (I.P) 30 min before training. Immediately after training the rats were injected with glucose (100 mg/kg, I.P). Retention was tested 2 days later. The results indicate that systemic post-training injection of glucose improved memory storage and this effect was attenuated and enhanced by pretreatment of minoxidil and glibenclamide, respectively. The drug minoxidil or glibenclamide alone did not significantly affect memory storage. This shows that K-ATP channels mediate the memory improving effects of systemic glucose.