1887

Abstract

The cyclin-dependent kinase inhibitor p27 plays a key role in controlling cell proliferation. Here we show that p27 is commonly down-regulated in B-cells immortalized by Epstein–Barr virus (EBV) (lymphoblastoid cell lines, LCLs). The significance of this event for the immortal phenotype of LCLs is implied by a requirement for active cdk2-containing complexes for continued proliferation, and by the ability of the residual p27 to associate with cdk2. The mechanism of p27 attenuation is post-translational, but inhibitor studies reveal that the mechanism does not rely heavily on the proteasome. Instead we find that LCLs contain an activity that cleaves a caspase recognition site present in p27 (DPSD). The activity is not associated with apoptosis and closely resembles a proliferation-associated caspase activity we previously described in the EBV-negative B-lymphoma-derived cell line BJAB. Importantly, proliferating LCLs contain a p27 product that is consistent with cleavage at this site. Inhibition of caspase(s) modulates p27 expression and strongly inhibits proliferation of IB4 cells. This inhibitor profile is identical to that displayed by the DPSD-directed caspase present in BJAB cells, suggesting that the caspase may fulfil a general role in controlling p27 expression in immortal lymphoid cell lines. Thus, apoptosis-independent cleavage appears to contribute to the maintenance of the low basal levels of p27 in B-cells immortalized by EBV.

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2001-12-01
2020-01-27
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