Signal transduction during environmental stress: InsP8 operates within highly restricted contexts.
Genetic manipulation of diphosphoinositol polyphosphate synthesis impacts many biological processes (reviewed in S.B. Shears, Biochem. J. 377, 2004, 265-280). These observations lacked a cell-signalling context, until the recent discovery that bis-diphosphoinositol tetrakisphosphate ([PP]2-InsP4 or "InsP8") accumulates rapidly in mammalian cells in response to hyperosmotic stress (X. Pesesse, K. Choi, T. Zhang, and S. B. Shears J. Biol. Chem. 279, 2004, 43378-43381). We now investigate how widely applicable is this new stress-response. [PP]2-InsP4 did not respond to mechanical strain or oxidative stress in mammalian cells. Furthermore, despite tight conservation of many molecular stress responses across the phylogenetic spectrum, we show that cellular [PP]2-InsP4 levels do not respond significantly to osmotic imbalance, heat stress and salt toxicity in Saccharomyces cerevisiae. In contrast, we show that [PP]2-InsP4 is a novel sensor of mild thermal stress in mammalian cells: [PP]2-InsP4 levels increased 3-4 fold when cells were cooled from 37 to 33 degrees C, or heated to 42 degrees C. Increases in [PP]2-InsP4 levels following heat-shock were evident <5 min, and reversible (t(1/2)=7 min) once cells were returned to 37 degrees C. These responses were blocked by pharmacological inhibition of the ERK/MEK pathway. Additional control processes may lie upstream of [PP]2-InsP4 synthesis, which was synergistically activated when heat stress and osmotic stress were combined. Our data add to the repertoire of signaling responses following thermal challenges, a topic of current interest for its possible therapeutic value.
Choi
Kuicheon
K
Inositide Signaling Group, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, PO Box 12233, NC 27709, USA.
Mollapour
Elahe
E
Shears
Stephen B
SB
D017766:Acid Anhydride Hydrolases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D018869:Heat-Shock Response; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009997:Osmotic Pressure; D018384:Oxidative Stress; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D029701:Saccharomyces cerevisiae Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D017856:Phosphotransferases (Phosphate Group Acceptor); C098863:KCS1 protein, S cerevisiae; D017766:Acid Anhydride Hydrolases; C116368:diphosphoinositol polyphosphate phosphohydrolase