Delineation of the caspase-9 signaling cascade

Alan D Guerrero, Min Chen, Jin Wang

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

In the intrinsic apoptosis pathway, mitochondrial disruption leads to the release of multiple apoptosis signaling molecules, triggering both caspase-dependent and -independent cell death. The release of cytochrome c induces the formation of the apoptosome, resulting in caspase-9 activation. Multiple caspases are activated downstream of caspase-9, however, the precise order of caspase activation downstream of caspase-9 in intact cells has not been completely resolved. To characterize the caspase-9 signaling cascade in intact cells, we employed chemically induced dimerization to activate caspase-9 specifically. Dimerization of caspase-9 led to rapid activation of effector caspases, including caspases-3, -6 and -7, as well as initiator caspases, including caspases-2, -8 and -10, in H9 and Jurkat cells. Knockdown of caspase-3 suppressed caspase-9-induced processing of the other caspases downstream of caspase-9. Silencing of caspase-6 partially inhibited caspase-9-mediated processing of caspases-2, -3 and -10, while silencing of caspase-7 partially inhibited caspase-9-induced processing of caspase-2, -3, -6 and -10. In contrast, deficiency in caspase-2, -8 or -10 did not significantly affect the caspase-9-induced caspase cascade. Our data provide novel insights into the ordering of a caspase signaling network downstream of caspase-9 in intact cells during apoptosis.

Original languageEnglish (US)
Pages (from-to)177-86
Number of pages10
JournalApoptosis
Volume13
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Apoptosis
  • Caspase 9
  • Caspases
  • Cell Line, Tumor
  • Cytochromes c
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Mitochondria
  • RNA Interference
  • Signal Transduction
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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