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VERSION:2.0
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SUMMARY:The role of cIAPs and their regulation of RIP Kinases in necroptos
 is and inflammation signalling pathways - Do cIAP knock-out mice age prema
 turely?
DTSTART:20131218T143000
DTEND:20131218T153000
DTSTAMP:20260916T211918Z
UID:f893d89d7110f3bb666660af3b8abead42818a07d802c18184a7a887
CATEGORIES:Conferences - Seminars
DESCRIPTION:John Silke\, Ph.D.\, The Walter and Eliza Hall Institute\, Par
 kville\, Victoria\, Australia\nDetails: see website at http://www.wehi.edu
 .au/faculty_members/associate_professor_john_silke\nA seminar of the Lausa
 nne Integrative Metabolism and Nutrition Alliance (LIMNA)\nAbstract:\nNecr
 optosis is a genetically programmed cell death that is caspase independent
  and RIPK3 and MLKL dependent. In distinction to apoptosis\, necroptotic c
 ell death is believed to provoke an inflammatory response and loss of this
  cell death pathway has been shown to ameliorate some inflammatory disease
 s. We have shown that cIAP1 and cIAP2 double knock-out mice die at embryon
 ic stage E10.5. This is the same developmental stage that any of the caspa
 se-8\, cFLIP or FADD knock-out mice die and it is likely that they all die
  from the same causes because each knock-out is protected by combined loss
  of the necroptosis inducing kinase RIPK3. Furthermore\, this embryonic de
 ath is driven by TNFR1 signaling because combined loss of Tnfr1 also prote
 cts these mice. Unfortunately the early embryonic death of these mice make
 s it difficult to determine the underlying cause and in particular to dist
 inguish whether necroptotic death causes a lethal inflammation or alternat
 ively whether necroptosis is a epiphenomenon of an underlying inflammatory
  problem. We have now analysed Ripk1-/- mice\; these knock-outs are one of
  the last major components of the TNFR1 signaling complex to be investigat
 ed in detail and the reason for their perinatal death is unknown. Using a 
 host of knock-out mice we show that death at birth is due to a sterile but
  MyD88 dependent systemic inflammatory syndrome that is driven by RIPK1/RI
 PK3/MLKL mediated necroptotic cell death. In addition I intend to discuss 
 the phenotype of the tissue specific cIAP knock-out animals that are viabl
 e but which develop an inflammatory syndrome that leads to their early dea
 th. This inflammatory syndrome is also highly likely to be driven by TNFR1
 /RIPK1/RIPK3 induced necroptotic cell death. Together these studies demons
 trate the critical role that IAPs play to regulate the RIP kinases to prev
 ent necroptosis and inflammation and suggest that targeting the necroptosi
 s cell death pathway could be useful therapeutically. Time permitting I'd 
 like to mention some progress we've made in this area.
LOCATION:AI 1 153 http://map.epfl.ch/?room=ai1153
STATUS:CONFIRMED
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