Sg. Kim et al., Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-beta 1-induced apoptosis in human gastric cancer cells, ONCOGENE, 20(10), 2001, pp. 1254-1265
Although TGF-beta1, a growth inhibitor, is known to also induce apoptosis,
the molecular mechanism of this apoptosis is largely undefined, Here, we id
entify the mechanism of TGF-beta1-induced apoptosis in SNU-16 human gastric
cancer cells. Cell cycle and TUNEL analysis showed that, upon TGF-beta1 tr
eatment, cells mere initially arrested at the G1 phase and then driven into
apoptosis, Of note, caspase-3 was activated in accordance with TGF-beta1-i
nduced G1 arrest, Activated caspase-3 is targeted to cleave p21(cip1), p27(
kip1), and Rb, which play important roles in TGF-beta -induced G1 arrest, i
nto;inactive fragments. Subsequently, Cdk2 was aberrantly activated due to
the cleavage of p21 and p27, We found that the inhibition of Cdk2 activity
efficiently blocks TGF-beta1-induced apoptosis, whereas it did; not prevent
caspase-3 activation or the subsequent cleavage of target proteins, In con
trast, the suppression of caspase-3 activity inhibited the cleavage of targ
et proteins, the activation of Cdk2, and the induction of apoptosis. Taken
together, our results suggest that activation of caspase-3 by TGF-beta1 may
initiate the conversion from G1 cell cycle arrest to apoptosis via the cle
avage of p21, p27 and Rb, which in turn causes Cdk2 activation and, most si
gnificantly, Cdk2 activation as a downstream effector of caspase is a criti
cal step for the execution TGF-beta1-induced apoptosis.