PT  - JOURNAL ARTICLE
AU  - Roberto R. Rosato
AU  - Jorge A. Almenara
AU  - Chunrong Yu
AU  - Steven Grant
TI  - Evidence of a Functional Role for p21<em><sup>WAF1</sup></em><sup>/</sup><em><sup>CIP1</sup></em> Down-Regulation in Synergistic Antileukemic Interactions between the Histone Deacetylase Inhibitor Sodium Butyrate and Flavopiridol
AID  - 10.1124/mol.65.3.571
DP  - 2004 Mar 01
TA  - Molecular Pharmacology
PG  - 571--581
VI  - 65
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/65/3/571.short
4100  - http://molpharm.aspetjournals.org/content/65/3/571.full
SO  - Mol Pharmacol2004 Mar 01; 65
AB  - The functional significance of disruption of p21WAF1/CIP1 induction by flavopiridol (FP) in human leukemia cells (Jurkat) exposed to the histone deacetylase (HDAC) inhibitor sodium butyrate (SB) was investigated. Coexposure of leukemic cells to FP blocked SB-mediated induction of p21WAF1/CIP1 and resulted in a marked increase in mitochondrial injury, activation of procaspases-3 and -8, Bid cleavage, and PARP degradation. Enforced expression of p21WAF1/CIP1 (i.e., in Jurkat cells inducibly expressing p21WAF1/CIP1 under the control of a doxycycline-responsive promoter) partially but significantly reduced cytochrome c and apoptosis-inducing factor release, loss of mitochondrial membrane potential, caspase-3 and -8 activation, Bid cleavage, poly(ADP-ribose)polymerase (PARP) degradation, and apoptosis in response to SB/FP. Furthermore, increasing expression of p21WAF1/CIP1 (i.e., by culturing cells in the presence of higher concentrations of doxycycline) rendered cells more resistant to SB/FP-mediated lethality. Enforced expression of p21WAF1/CIP1 did not modify SB/FP-mediated JNK activation or generation of reactive oxygen species. Consistent with these results, Jurkat cells stably expressing a p21WAF1/CIP1 nuclear localization mutant (p21ΔNLS) were also resistant to SB/FP-mediated mitochondrial injury, activation of procaspases-3 and -8, PARP cleavage, and apoptosis. Finally, enforced expression of full-length or ectopic expression of ΔNLS p21WAF1/CIP1 increased the amount of p21WAF1/CIP1 coimmunoprecipitating with procaspase-3. Together, these findings suggest that interruption of HDAC-mediated p21WAF1/CIP1 induction by FP plays a significant functional role in potentiating apoptosis, possibly by preventing the formation of a procaspase-3/p21WAF1/CIP1 complex.