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SUMMARY:COP1 E3-ligase – A journey from Photomorphogenesis to the heartl
 and of cancer - Dr. Vishva M. Dixit
DTSTART:20140714T120000Z
DTEND:20140714T130000Z
UID:TALK53394@talks.cam.ac.uk
CONTACT:38267
DESCRIPTION:SUMMARY OF PAST RESEARCH\n \nApoptosis was a mysterious proces
 s in the early nineties. A debate raged as to how the TNF receptor TNFR1 a
 nd its close homologue Fas engaged the suicide pathway. The first breakthr
 ough was the demonstration from the Dixit laboratory that a cysteine prote
 ase (now termed caspase) was a component of the death receptor-induced apo
 ptotic pathway (Tewari\, JBC\, 1995\, citations: 656). These observations 
 set the stage for the identification of YAMA\, or caspase-3\, as the key d
 ownstream executioner protease (Tewari\, Cell\, 1995\, citations: 2\,174)\
 , although this then begged the question of how it was engaged by death re
 ceptors.  Other surface receptors functioned as ion channels or by alterin
 g intracellular phosphorylation events but death receptors signaled apopto
 sis by an entirely new mechanism. Specifically\, an adapter protein termed
  FADD recruited and activated an initiating death protease termed FLICE/ca
 spase-8 (Chinnaiyan\, Cell\, 1995\, citations: 2\,434 and Muzio\, Cell\, 1
 996\, citations: 2\,960). In other words\, the second messenger emanating 
 from the death receptor was a protease! These papers\, designated citation
  classics\, resulted in Dr. Dixit being the second most highly cited scien
 tist in 1996.\n \nSubsequently\, his laboratory promulgated the “induced
  proximity model” as a mechanism for the activation of caspase zymogens 
 (Muzio\, JBC\, 1998\, citations\; 1\,053)\, showed that the FADD/caspase-8
  pathway was indeed the central apoptotic conduit used by all death recept
 ors (Pan\, Science\, 1997\, citations: 1\,519)\, revealed TRAF3 to be a CD
 40 signaling adaptor (Hu\, JBC\, 1994\; citations: 344)\, demonstrated tha
 t MyD88 was a key adaptor in IL-1 signaling (Muzio\, Science\, 1997\, cita
 tions: 977)\, discovered Paracaspases and Metacaspases\, one of which play
 s a central role in MALT lymphoma (Uren\, Mol Cell\, 2000\, citations: 792
 )\, provided the first evidence of ephrin system involvement in angiogenes
 is (Pandey\, Science\,1995\, citations: 368) and established that NOD prot
 eins possessing a death-fold are critical components of the inflammasome c
 omplex (Mariathasan\, Nature\, 2006\, citations: 1\,232). A20\, an increas
 ingly important negative regulator of NF-kappaB signaling incontrovertibly
  linked to human autoimmune disorders\, was first discovered and character
 ized by his laboratory (Opipari\, JBC\, 1990\, citations: 310 and Krikos\,
  JBC\, 1992\, citations: 340) and shown to possess ubiquitin editing activ
 ity (Wertz\, Nature\, 2004\, citations: 1009) using isopeptide-linkage spe
 cific antibodies (Newton\, Cell\, 2008\, citations: 293). Most recently\, 
 his group has discovered the non-canonical Inflammasome pathway that respo
 nds to the presence of intracellular LPS independent of toll-like receptor
 s (Kayagaki\, Nature\, 2011 and Kayagaki\, Science\, 2013).\n \nMuch of wh
 at is described herein is documented in three accounts published in Nature
  (2008\, 453:271-273)\, Nature Cell Biology (2010\, 12(5): 415) and The Jo
 urnal of Immunology (2013\, 190:3-4).  These accounts highlight the pervas
 ive excitement in the heydays of apoptosis research and Dr. Dixit’s pivo
 tal role.\n\nHosted by the Director of the Babraham Institute - Prof Micha
 el Wakelam
LOCATION:The Babraham Institute - Brian Heap Seminar Room
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