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PNAS 99 (10): 6871-6876

Copyright © 2002 by the National Academy of Sciences.


Cyclin D3 activates Caspase 2, connecting cell proliferation with cell death

Andrew R. Mendelsohn, Janice D. Hamer, Zhaoyuan Bill Wang, and Roger Brent*

Molecular Sciences Institute, 2168 Shattuck Avenue, Berkeley, CA 94704

Received for publication June 11, 2001.

Abstract: Precancerous cells that enter S phase without appropriate growth and viability factors undergo programmed cell death, suggesting that apoptosis may help guarantee organismic integrity [Evan, G. & Littlewood, T. (1998) Science 281, 1317–1322]. However, the connection between proliferation and cell death has remained unclear. Here, we show that the positive cell cycle regulator cyclin D3 [Matsushime H., Roussel M. F., Ashmun, R. A. & Sherr, C. J. (1991) Cell 65, 701–713] interacts with the death enzyme Caspase 2 [Wang, L., Miura, M., Bergeron, L., Zhu, H. & Yuan, J. (1994) Cell 78, 739–750]. Directed expression of cyclin D3 and Caspase 2 in human cells potentiated apoptosis compared with expression of Caspase 2 alone. Cyclin D3 expression increased the amount of cleaved (active) Caspase 2. We describe a PCR mutagenesis/ligation/two-hybrid/green fluorescent protein approach that facilitates the isolation of missense mutant proteins defective in interaction with particular partners absent other phenotypes or knowledge of the system. We used this approach to isolate Caspase 2 mutants that did not bind cyclin D3 (noninteractors). Noninteractors were sensitive to apoptosis-dependent proteolysis, but did not potentiate apoptosis. Noninteractors did not block apoptosis caused by wild-type Caspase 2. Our results are consistent with the idea that an interaction with cyclin D3 may stabilize Caspase 2, and suggest that a physical interaction between cyclin D3 and Caspase 2 connects the genetic networks that govern cell-cycle progression with those that govern cell death.

* To whom reprint requests should be addressed. E-mail: brent{at}

Edited by Ronald W. Davis, Stanford University School of Medicine, Stanford, CA, and approved February 11, 2002

This paper was submitted directly (Track II) to the PNAS office.

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