Etiology and Pathogenesis > Apoptosis

Cell, Volume 125, Issue 7, 30 June 2006, Pages 1333-1346. doi:10.1016/j.cell.2006.05.026. Available online 29 June 2006

Abstract
Intracellular Nucleotides Act as Critical Prosurvival Factors by Binding to Cytochrome C and Inhibiting Apoptosome

Dhyan Chandra1,*, Shawn B. Bratton2, Maria D. Person2, Yanan Tian3, Angel G. Martin4, Mary Ayres5, Howard O. Fearnhead4, Varsha Gandhi5 and Dean G. Tang1, 6,*

1Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA. 2Division of Pharmacology/Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA. 3Department of Veterinary Physiology and Pharmacology, MS 4466, Texas A&M University, College Station, TX 77843, USA. 4Apoptosis Section, Laboratory of Protein Dynamics and Signaling, NCI-Frederick, Frederick, MD 21702, USA. 5Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. 6Program in Molecular Carcinogenesis of Graduate School for Biomedical Science, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
* Corresponding Author. Ph: (512) 237-9575; Fax: (512) 237-2475.
Received 22 June 2005;  revised 6 January 2006;  accepted 3 May 2006.  Published: June 29, 2006.


Cytochrome c (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.

Copyright © 2006 Elsevier B.V.
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