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  • Original Paper
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Exploitation of a non-apoptotic caspase to regulate the abundance of the cdkI p27KIP1 in transformed lymphoid cells

Abstract

Expression of the cyclin dependent kinase inhibitor p27KIP1 is intimately linked to the control of proliferation, and is itself regulated by transcription, translation, phosphorylation, protein stability or sequestration. p27KIP1 is also regulated during apoptosis; cleavage occurs at DPSD139S and ESQD108V, by a sub-set of Z-VAD-fmk-sensitive caspases. We have identified a related but distinct mechanism that regulates p27KIP1 in proliferating lymphoid cell lines. In a B-lymphoid cell line (BJAB), the abundance of p27KIP1 oscillates inversely to proliferation; loss of full-length p27KIP1 correlates with the appearance of a truncated version corresponding to cleavage at DPSD139S. A direct correlation exists between the appearance of truncated p27KIP1 and the presence of an activity able to cleave peptides representing DPSD139S and a caspase-8 substrate (Ac-IETD-AMC) in vitro. This activity is inhibited by Ac-IETD-CHO but not Z-VAD-fmk in vitro. Furthermore a requirement for caspase-8 has been excluded. The activity differs from the apoptosis related p27KIP1-cleaving activity; indeed few cells undergoing apoptosis are present in the population of proliferating cells. The activity is further distinguished by its inability to cleave a peptide based on ESQD108V in vitro, together with the lack of a corresponding cleavage product in vivo. Inhibition of the caspase activity in vivo promotes an accumulation of full length p27KIP1, as well as a decrease in cell proliferation. Together these studies highlight the importance of non-apoptotic caspases in regulating p27KIP1 in transformed lymphoid cells.

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Acknowledgements

We would like to thank J Blenis and P Juo for generously providing the Jurkat A3 and Jurkat 9.2 cell lines and J Massague for providing the human p27KIP1 cDNA. We are grateful to S Morley for helpful discussions during the course of this work. This work was funded by grants from the Leukaemia Research Fund, the Wellcome Trust and the Medical Research Council.

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Frost, V., Al-Mehairi, S. & Sinclair, A. Exploitation of a non-apoptotic caspase to regulate the abundance of the cdkI p27KIP1 in transformed lymphoid cells. Oncogene 20, 2737–2748 (2001). https://doi.org/10.1038/sj.onc.1204367

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