PubMed · 7974328
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P Harris. 1994. Evolution and the pulmonary circulation.. https://doi.org/10.1136/thx.49.suppl.s5
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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.
Proton-ATPase was localized to mitochondria-rich cells in the interlamellar region of the gills of the elasmobranch, Squalus acanthias. Localization was accomplished using a polyclonal antibody specific for the 70 kDa subunit of the (V-type) proton-ATPase as confirmed by Western blot analysis. In addition, significant levels of N-ethymaleimide sensitive ATPase activity (0.116 +/- 0.026 mumol Pi.mg-1 protein.h-1) were also measured in crude gill membrane preparations. These data provide, for the first time, direct evidence of the localization of elements possibly involved in branchial acid-base (or ionic) regulation in elasmobranchs.