Article

A novel function of eIF2alpha kinases as inducers of the phosphoinositide-3 kinase signaling pathway.

Lady Davis Institute, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, QC, Canada H3T 1E2.
Molecular Biology of the Cell (impact factor: 4.94). 10/2007; 18(9):3635-44. DOI:10.1091/mbc.E07-01-0053 pp.3635-44
Source: PubMed

ABSTRACT Phosphoinositide-3 kinase (PI3K) plays an important role in signal transduction in response to a wide range of cellular stimuli involved in cellular processes that promote cell proliferation and survival. Phosphorylation of the alpha subunit of the eukaryotic translation initiation factor eIF2 at Ser51 takes place in response to various types of environmental stress and is essential for regulation of translation initiation. Herein, we show that a conditionally active form of the eIF2alpha kinase PKR acts upstream of PI3K and turns on the Akt/PKB-FRAP/mTOR pathway leading to S6 and 4E-BP1 phosphorylation. Also, induction of PI3K signaling antagonizes the apoptotic and protein synthesis inhibitory effects of the conditionally active PKR. Furthermore, induction of the PI3K pathway is impaired in PKR(-/-) or PERK(-/-) mouse embryonic fibroblasts (MEFs) in response to various stimuli that activate each eIF2alpha kinase. Mechanistically, PI3K signaling activation is indirect and requires the inhibition of protein synthesis by eIF2alpha phosphorylation as demonstrated by the inactivation of endogenous eIF2alpha by small interfering RNA or utilization of MEFs bearing the eIF2alpha Ser51Ala mutation. Our data reveal a novel property of eIF2alpha kinases as activators of PI3K signaling and cell survival.

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  • Article: Methodologic issues in the use of bleeding as an outcome in transfusion medicine studies.
    Nancy M Heddle, Richard J Cook, Kathryn E Webert, Christopher Sigouin, Paolo Rebulla
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    ABSTRACT: Prophylactic platelet transfusions are given to thrombocytopenic patients to prevent bleeding. The benefit of platelet transfusions has frequently been assessed by measuring the count increment; however, more recently, an assessment of bleeding has been used because it is a more clinically relevant outcome measure. The purpose of this study was to identify platelet transfusion trigger studies that used bleeding as an outcome measure, compare and contrast methods used to document bleeding and analyze bleeding outcomes, and identify and discuss methodologic issues to consider when bleeding is used as a study outcome. A systematic search to identify platelet transfusion trigger studies was performed. Relevant articles were reviewed to identify how bleeding data was captured and analyzed, and methodologic considerations were identified. Seven articles meeting the predefined entry criteria were identified. Methods used to document bleeding included chart review and clinical assessment. The frequency of assessment and the type of personnel performing the assessment were variable. Four approaches to analysis were identified: descriptive; comparison of the proportions of patients having at least one bleed; comparison of patient days with bleeding expressed as a proportion of the total days at risk of bleeding; and time-to-event (first bleed) analysis. Methodologic issues for consideration when designing a clinical study with bleeding as the outcome measure included approaches to minimize bias in the documentation and classification of bleeding and selection of an analysis approach that is appropriate to the question being asked. The need for development of a valid and reliable bleeding scale was also identified.
    Transfusion 07/2003; 43(6):742-52. · 3.22 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

Akt/PKB-FRAP/mTOR pathway
 
cellular processes
 
conditionally active form
 
conditionally active PKR
 
eIF2alpha kinase
 
eIF2alpha kinase PKR acts upstream
 
eIF2alpha kinases
 
eIF2alpha phosphorylation
 
eIF2alpha Ser51Ala mutation
 
endogenous eIF2alpha
 
environmental stress
 
eukaryotic translation initiation factor eIF2
 
novel property
 
PI3K signaling
 
PI3K signaling activation
 
PI3K signaling antagonizes
 
promote cell proliferation
 
protein synthesis inhibitory effects
 
signal transduction
 
various types
 

Shirin Kazemi