p27(KIP1) is down-regulated by two different mechanisms in human lymphoid cells undergoing apoptosis

The cyclin-dependent kinase inhibitor p27(KIP1) is a crucial component of t he mammalian restriction point, and as such is subject to multiple regulato ry mechanisms. It has recently been shown that the abundance of p27(KIP1) i s also regulated during apoptosis; p27K'P' is cleaved by a Z-VAD-fmk-sensit ive caspase during apoptosis induced by growth factor deprivation in endoth elial cells, and also following exposure of myeloid leukaemia cells to etop oside. Here, we investigate p27(KIP1) regulation in B- and T-lymphoid cells undergoing apoptosis, We observe that p27(KIP1) is down-regulated followin g exposure to a variety of apoptotic stimuli including an agonistic anti-Fa s antibody, cycloheximide and etoposide. Further investigation revealed the existence of two different routes of p27K'P' regulation in lymphoid cells undergoing apoptosis. The first pathway is utilized by lymphoid cells stimu lated through Fas, is abrogated in a caspase-8-deficient T-cell line, and i s blocked by the caspase inhibitors z-VAD-fmk and Boc-D-fmk. In contrast, t he loss of p27(KIP1) in cells exposed to cycloheximide and etoposide occurs in the absence of caspase-8 or any z-VAD-fmk- or Boc-D-fmk-sensitive caspa se activities. Thus the down-regulation of p27(KIP1) is a common occurrence in lymphoid cells undergoing apoptosis but, depending on the apoptotic tri gger, this can be affected by two different mechanisms.