Caspase 9 and Mitochondrial Apoptosis Regulation

Fri, 01/18/2013 - 07:30

Caspase 9 (also termed ICE-LAP6, Mch6, Apaf-3) is a member of cysteine protease family of caspases and is encoded by the CASP9 gene in humans. Caspase-9 is involved in mitochondrial apoptosis pathway and is an initiator caspase. Pro-caspase-9 is activated when binding with Apaf-1 via their respective N-terminal CED-3 homologous domains in the presence of dATP and Cytochrome c (1). Activated Caspase-9 then cleaves downstream pro-Caspase 3 and Caspase 7 and initiates apoptosis cascade which leads to DNA fragmentation and cell death.

Western Blot: Caspase 9 Antibody

It has been reported that Caspase-9 activity is regulated by phosphorylation: the kinase Akt and p21-Ras (an Akt activator) induce phosphorylation of pro-Caspase-9 at Ser196 (2). This phosphorylation event inhibits proteolytic processing of pro-Caspase-9.  Mutant pro-Caspase-9 (Ser196Ala) was resistant to Akt-mediated phosphorylation in cells, resulting in Akt-resistant induction of apoptosis.

Collective evidence suggests that Caspase-9 function is critical for apoptosis during normal development of the central nervous system. Homozygous Caspase-9 knockout mice (Casp9 -/-) is in the most cases lethal, and were consistently smaller than control littermates (3). These mice often have a significantly enlarged and malformed cerebrum caused by a reduction of apoptosis during early brain development, and often developed brain tissue outside of skull. Moreover, mutant embryonic stem cells (Casp9 -/-) and fibroblasts (Casp9 -/-) were shown resistance to several stimuli, such as UV and gamma irradiation (4). Mutant thymocytes (Casp9 -/-), however, were resistance to dexamethasone- and gamma irradiation-induced apoptosis but sensitive to apoptosis induced by UV irradiation or anti-CD95.

IN THE NEWS: (Nov 3, 2011) Dr Antonio Di Stasi from the Texas Children’s Hospital and colleagues reported that the incorporation of inducible Caspase-9 (iCasp9) can be used to stimulate apoptosis in patients receiving adoptive cell therapy. They applied an ‘inducible T-cell iCasp9 safety switch’ that is based on the fusion of human Caspase-9 to a modified human FK-binding protein, allowing conditional dimerization. Therefore when exposed to a synthetic dimerizing drug, the iCasp9 becomes activated and results in a rapid cell death. Five patient ages between 3 and 17 years who had undergone stem-cell transplantation for relapsed leukemia were treated with these genetically modified T cell. A single dose of dimerizing drug AP 1903 given to four patients eliminated more than 90% of the modified T cells within 30 minutes. This result indicates that the iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical application.

  1. PMID: 9390557
  2. PMID: 9812896
  3. PMID: 10687948
  4. PMID: 9708736

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