Serine/threonine phosphatase regulation of phosphorylation-mediated intracellular signaling controls a number of important processes in mammalian cells. In this study, we show that constitutively active
protein phosphatase 2A (PP2A), which is a
serine/threonine phosphatase, is essential for T
leukemia cell survival. Jurkat and CCRF-CEM T
leukemia cells treated with the PP2A-selective inhibitor
okadaic acid (OA) showed a dose- and time-dependent induction of apoptosis, as indicated by loss of mitochondrial transmembrane potential (delta psi(m)), cleavage-induced activation of
caspase-3, -8, and -9, and DNA fragmentation. In addition,
caspase-8 or
caspase-9 inhibition with
z-IETD-fmk or
z-LEHD-fmk, respectively, largely prevented OA-induced apoptosis. Although OA treatment did not affect constitutive Bcl-2 expression, overexpression of Bcl-2 prevented both OA-induced DNA fragmentation and dissipation of delta psi(m). Furthermore, inhibition of
caspase-3, -8, or -9 partially protected against OA-induced loss of delta psi(m). In addition,
caspase-9 and
caspase-3 inhibition largely prevented
procaspase-3 and
procaspase-8 cleavage, respectively, while
caspase-8 inhibition partially interfered with
procaspase-9 cleavage in OA-treated T
leukemia cells. Thus, PP2A inhibition triggered the intrinsic pathway of apoptosis, which was enhanced by a mitochondrial feedback amplification loop. PP2A has also been implicated in the regulation of
p38 mitogen-activated protein kinase (MAPK). Co-immunoprecipitation analysis revealed a physical association between the catalytic subunit of PP2A and
p38 MAPK in T
leukemia cells. Moreover, OA treatment caused
p38 MAPK to be phosphorylated in a dose- and time-dependent fashion, indicating that PP2A prevented
p38 MAPK activation. Although
p38 MAPK activation usually promotes apoptosis, pharmacologic inhibition of
p38 MAPK exacerbated OA-induced DNA fragmentation and loss of delta psi(m) in T
leukemia cells, suggesting that, in this instance, the
p38 MAPK signaling pathway promoted cell survival. Collectively, these findings indicate that PP2A and
p38 MAPK have coordinate effects on signaling pathways that regulate the survival of T
leukemia cells.