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Regulation of p27^KIP1 in Epstein–Barr virus-immortalized lymphoblastoid cell lines involves non-apoptotic caspase cleavage

School of Biological Sciences, University of Sussex, Brighton, East Sussex, BN1 9QG, UK¹

Author for correspondence: Alison Sinclair. Fax +44 1273 678433. e-mail A.J.Sinclair{at}sussex.ac.uk

The cyclin-dependent kinase inhibitor p27^KIP1 plays a key role in controlling cell proliferation. Here we show that p27^KIP1 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^KIP1 to associate with cdk2. The mechanism of p27^KIP1 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^KIP1 (DPSD¹³⁹). 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^KIP1 product that is consistent with cleavage at this site. Inhibition of caspase(s) in vivo modulates p27^KIP1 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^KIP1 expression in immortal lymphoid cell lines. Thus, apoptosis-independent cleavage appears to contribute to the maintenance of the low basal levels of p27^KIP1 in B-cells immortalized by EBV.

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