PubMed · 6268396
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S Jacobs, P Cuatrecasas. 1981. Insulin receptor: structure and function.. https://doi.org/10.1210/edrv-2-3-251
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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.
The in vivo synthesis of an F1F0-ATPase hybrid in Escherichia coli strain PEF42 which harbours the genes for the Propionigenium modestum subunits a, b, c, and delta, a gene for hybrid alpha subunit with the N-terminal portion (amino acids 1 to 173) of P. modestum and the C-terminal region (amino acids 176 to 513) from E. coli, and the genes for the E. coli subunits beta, gamma and epsilon, yielded a functional enzyme complex. This hybrid ATPase coupled ATP synthesis to Na+ transport and required Na+ for growth on succinate. After random mutagenesis of the P. modestum genes of strain PEF42, clones were selected that grew on succinate in the absence of Na+. A double-mutation cPhe84Leu, cLeu87Val that was found in several of these clones, was introduced by site specific mutagenesis into the parent strain PEF42. The resulting strain E. coli MPC8487 also exhibited Na(+)-independent growth on succinate, showing that the double mutation is the only reason for the new phenotype. The mutation causes a change of the coupling ions of the hybrid ATPase from Na+ in strain PEF42 to H+ in strain MPC8487. This conclusion was supported by the biochemical properties of the ATPase from strain MPC8487. Unlike the parent enzyme, the mutated ATPase was not activated by Na+, but retained activation by Li+. The pH optimum of the mutated ATPase (in the absence of Na+ or Li+) was shifted from pH 6.5 to pH 7.5, and the specific ATPase activity of the cell membranes increased about fourfold over that found in membranes of the parent cells. The mutated ATPase pumped protons or Li+ after reconstitution into proteoliposomes, and the transport of both cations was not affected by Na+. The double mutation in the c subunit thus results in the loss of Na+ binding, retention of Li+ binding and an improvement of H+ binding.