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At least 91 records · Page 5Linked to original sources
PubMed2006

OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells.

We determined one mechanism by which the putative phosphoinositide-dependent kinase (PDK)-1 inhibitor 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide (OSU-03012) killed primary human glioma and other transformed cells. OSU-03012 caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function. OSU-03012 promoted cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 and ionizing radiation caused an additive, caspase-independent elevation in cell killing in 96-h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner, combined exposure to OSU-03012 with a mitogen-activated protein kinase kinase 1/2 inhibitor, phosphoinositide 3-kinase/AKT inhibitors, or parallel molecular interventions resulted in a greater than additive induction of cell killing that was independent of AKT activity and caspase function. OSU-03012 lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK. OSU-03012 promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BH3-interacting domain (BID) function, overexpression of BCL(XL), and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria. In protein kinase R-like endoplasmic reticulum kinase-/- cells, the lethality of OSU-03012 was attenuated which correlated with reduced cleavage of BID and with suppression of cathepsin B and AIF release into the cytosol. Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2001

Protein synthesis. The perks of balancing glucose.

What do the regulation of translation initiation and glucose metabolism have to do with each other? Quite a lot, it seems, according to Sonenberg and Newgard in their Perspective. They discuss new findings that identify the kinase responsible for inactivating eIF2--a factor that is required for translation initiation (and hence protein synthesis)--when the endoplasmic reticulum is under stress. Loss of this kinase results in destruction of insulin-producing b cells in the pancreas and dysregulation of glucose homeostasis.

Animals↗
PubMed2006

Divergent roles of IRE1alpha and PERK in the unfolded protein response.

The endoplasmic reticulum (ER) provides unique machinery for the folding and posttranslational modification of many secretory and transmembrane proteins in eukaryotic cells. The unfolded protein response (UPR) is a signal transduction network from the ER to the nucleus activated when the folding demand imposed by nascent, unfolded polypeptide chains exceeds the capacity of the ER protein folding machinery. In all eukaryotes the UPR maintains the physiological balance between folding demand and capacity of the ER by regulating adaptive responses to this stress situation. These include an increase in the folding capacity of the ER through induction of ER resident molecular chaperones and protein foldases, and a decrease in the folding demand on the ER by upregulation of ER associated degradation (ERAD), attenuation of general translation in metazoans, and stimulation of ER synthesis to dilute the unfolded protein load. In higher eukaryotes the UPR gained control over inflammatory and immune responses by controlling the activity of the transcription factor NF-kappaB to combat viral infections associated with an increased synthesis of viral glycoproteins. Similarly, in multicellular organisms apoptotic programs are controlled by the UPR to eliminate cells whose folding problems in the ER cannot be resolved by coordinated regulation of adaptive, inflammatory, and immune responses. In this review we will summarize our current understanding of signal transduction mechanisms involved in the mammalian UPR, and discuss examples to highlight the regulation of adaptive, inflammatory, immune, and apoptotic responses by the UPR.

Animals↗
PubMed1996

Perks for part timers.

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Health Benefit Plans, Employee↗