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Intracellular nucleotides act as critical prosurvival factors by binding to cyctochrome c and inhibiting apoptosome

  1. Author:
    Chandra, D.
    Bratton, S. B.
    Person, M. D.
    Tian, Y. A.
    Martin, A. G.
    Ayres, M.
    Fearnhead, H. O.
    Gandhi, V.
    Tang, D. G.

  2. Author Address

    Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Div Res, Smithville, TX 78957 USA. Univ Texas, Coll Pharm, Div Pharmacol & Toxicol, Austin, TX 78712 USA. Texas A&M Univ, Dept Vet Physiol & Pharmacol, College Stn, TX 77843 USA. NCI, Apoptosis Sect, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. Univ Texas, MD Anderson Canc Ctr, Program Mol Carcinogenesis, Grad Sch Biomed Sci, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA.;Chandra, D, Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Div Res, Sci Pk, Smithville, TX 78957 USA.;dhchandra@mdanderson.org dtang@mdanderson.org
    1. Year: 2006
    2. Date: Jun
  2. Journal: Cell
    1. 125
    2. 7
    3. Pages: 1333-1346
  4. Type of Article: Article
  5. ISSN: 0092-8674
  1. Abstract:

    Cytochromec(CC)-initiated Apaf-1 apoptosome formation represents a key initiating event in apoptosis. This process can be reconstituted in vitro with the addition of CC and ATP or dATP to cell lysates. How physiological levels of nucleotides, normally at high mM concentrations, affect apoptosome activation remains unclear. Here we show that physiological levels of nucleotides inhibit the CC-initiated apoptosome formation and caspase-9 activation by directly binding to CC on several key lysine residues and thus preventing CC interaction with Apaf-1. We show that in various apoptotic systems caspase activation is preceded or accompanied by decreases in overall intracellular NTP pools. Microinjection of nucleotides inhibits whereas experimentally reducing NTP pools enhances both CC and apoptotic stimuli-induced cell death. Our results thus suggest that the intracellular nucleotides represent critical prosurvival factors by functioning as natural inhibitors of apoptosome formation and a barrier that cells must overcome the nucleotide barrier to undergo apoptosis cell death.

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External Sources

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  2. DOI: 10.1016/j.cell.2006.05.026
  3. View record in Web of Science®
  4. WOS: 000239104500016

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