Janumyan, Yelena Melkum

ETD - Electronic Theses & Dissertations

Bcl-2/Bcl-xL Regulates Cell Cycle Through a Novel Mechanism in Addition to Cell Survival

Vanderbilt Electronic Thesis and Dissertation Archive

BCL-2/BCL-XL REGULATES CELL CYCLE THROUGH A NOVEL MECHANISM 
IN ADDITION TO CELL SURVIVAL  
By 
Yelena Melkum Janumyan 
 
Dissertation 
Submitted to the Faculty of the 
Graduate School of Vanderbilt University 
in partial fulfillment of the requirements 
for the degree of 
 
DOCTOR OF PHILOSOPHY 
in 
Cancer Biology 
December, 2005 
Nashville, Tennessee 
 
Approved: 
Professor Elizabeth Yang 
Professor Stephen Brandt 
Professor Josiane Eid 
Professor William Russell 
Professor James Sligh 
CANCER BIOLOGY 
 
BCL-2/BCL-XL REGULATES CELL CYCLE THROUGH A NOVEL MECHANISM 
IN ADDITION TO CELL SURVIVAL  
 
YELENA MELKUM JANUMYAN 
 
Dissertation under the direction of Professor Elizabeth Yang 
 
 Bcl-2 and Bcl-xL are anti-apoptotic and inhibit proliferation.  During cell cycle 
arrest, Bcl-2 or Bcl-xL expression causes elevation of the CDK inhibitor p27, decrease in 
cell size and RNA content.  This enhanced state of G0 results in delay of G0-G1 transition 
and S phase entry upon cell cycle stimulation.  We investigated the mechanism of the 
Bcl-2/Bcl-xL cell cycle function and the relationship between apoptosis regulation and 
cell cycle control. To assess the role of mitochondrial functions in Bcl-2/Bcl-xL-mediated 
cell cycle delay, we monitored ATP levels and found that cells expressing Bcl-2 or Bcl-xL 
exhibit a delay in peak ATP during cell cycle entry; however, exogenous elevation of 
ATP did not reverse the delay in cell cycle entry. In mtDNA-free 143B ρ0 cells defective 
in electron transport, Bcl-xL is still able to delay cell cycle entry but not enhance G0 
arrest. To determine whether enhanced G0 and subsequent delay in cell cycle are 
consequences of increased survival, we inhibited cell death by means other than Bcl-
2/Bcl-xL expression.  Increasing survival by caspase inhibition partially recapitulated the 
cell cycle arrest phenotype of Bcl-2/Bcl-xL, while cells expressing the survival kinase Akt 
exhibited none of the cell cycle phenotypes of Bcl-2/Bcl-xL.  These data indicate that the 
cell cycle delay by Bcl-2/Bcl-xL is not mediated through the regulation of ATP/ADP 
exchange, and does not require normal mitochondrial membrane potential.  Bcl-2/Bcl-xL 
may regulate quiescence partially through the inhibition of caspase-dependent apoptosis, 
but cell survival is not the sole mechanism of the cell cycle regulation by Bcl-2/Bcl-xL.  
In addition to inhibition of mitochondrial apoptosis, mechanisms requiring an intact 
electron transport chain are necessary for the full cell cycle function of Bcl-2/Bcl-xL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved       Date 


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Bcl-2/Bcl-xL Regulates Cell Cycle Through a Novel Mechanism in Addition to Cell Survival

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