PubMed · 7399480
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H J Morowitz. 1980. From soup to solid state.. https://doi.org/10.1080/21548331.1980.11946621
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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.
Apoptosis has been characterized as a regulated, energy-dependent process. Specific protein-phosphorylation events have been demonstrated previously to occur during apoptosis and may play an important role in the regulation of this death process. In this study, energy metabolism and protein phosphorylation during apoptosis of neuronal PC12 cells induced by nerve growth factor and serum deprivation was examined using [32P]Pi-labelling techniques. Although ATP levels were maintained at control levels during apoptosis, [32P]Pi incorporation into ATP was decreased significantly, coinciding with an almost identical decrease in Na+-dependent phosphate uptake. During neuronal PC12-cell apoptosis, increased phosphorylation of tau and high-molecular-weight (HMW) tau was observed within the epitope of Tau-1, a phosphate-dependent tau antibody that only recognizes the unphosphorylated form of its epitope. In addition, based on two-dimensional phosphopeptide mapping, [32P]Pi incorporation into a phosphopeptide of tau and HMW tau from apoptotic cells increased. Whereas [32P]Pi incorporation into total protein decreased to 23% of the control during apoptosis, [32P]Pi incorporation into tau and HMW tau was significantly higher, indicating a preferential phosphorylation of specific proteins during the apoptotic process. This study provides novel information about phosphate uptake, incorporation of [32P]Pi into ATP, and protein phosphorylation events during apoptosis.