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SUMMARY:Milstein Lecture 2014: Unfolded Protein Response in Health and Dis
 ease - Peter Walter\, University of California\, San Francisco 
DTSTART:20140630T151500Z
DTEND:20140630T170000Z
UID:TALK51070@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:The unfolded protein response is an intracellular signaling pa
 thway that adjusts the abundance and protein folding capacity of the endop
 lasmic reticulum according to need. The most conversed branch of the pathw
 ay mediated by the ER-resident transmembrane kinase/endoribonuclease Ire1\
 , was first discovered in Saccharomyces cerevisiae. It mediates signal tra
 nsduction via a non-conventional mRNA splicing mechanism that was since fo
 und conserved in all metazoan cells investigated. In response to accumulat
 ion of unfolded proteins in the ER\, mRNA splicing results in the producti
 on of a transcription factor (Hac1 in yeast and XBP1 in metazoan cells) th
 at up-regulates UPR targets genes\, which in turn enhance protein folding 
 in the ER to reestablish homeostasis. If homeostasis cannot be restored\, 
 cells commit to apoptosis. The UPR therefore makes life death decisions fo
 r the cell\, which connects it to numerous human diseases\, including inhe
 rited protein folding diseases\, neurodegeneration\, diabetes\, and cancer
 . In addition to the highly specific endonucleolytic activity of Ire1 for 
 HAC1/XBP1 mRNA\, a more pleiotropic activity of Ire1\, first discovered in
  Drosophila and then found in mammalian cells\, initiates degradation of a
  set of ER-bound mRNAs\, thereby reducing the load of proteins entering th
 e ER lumen by a process termed RIDD for regulated Ire1-dependent mRNA deca
 y. By contrast to other cells studied\, Schizosaccharomyces pombe encodes 
 no Hac1 homolog\, displays no transcriptional upregulation of UPR target g
 enes\, and uses RIDD as the sole mechanism to balance protein folding capa
 city with protein folding load. A single mRNA encoding the major ER chaper
 one BiP escapes decay after Ire1 cleavage in its 3’UTR. Truncated BiP mR
 NA is stabile despite its lack of a poly-A tail and is actively translated
 . Mechanistic aspects and evolutionary considerations will be discussed.\n
  Medical Institute
LOCATION:Max Perutz Lecture Theatre\, Medical Research Council (MRC) (MRC 
 Laboratory of Molecular Biol
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