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Volume 271, Number 37, Issue of September 13, 1996 pp. 22398-22406
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Calcium-dependent, Interleukin 1-converting Enzyme Inhibitor-insensitive Degradation of Lamin B₁ and DNA Fragmentation in Isolated Thymocyte Nuclei

(Received for publication, April 9, 1996, and in revised form, June 18, 1996)

From the Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Recent work suggests that the proteolytic degradation of the nuclear lamins is a common event in apoptosis, although the nature of the proteases involved is still not clear. Our previous work showed that the degradation of lamin B₁ in glucocorticoid-treated thymocytes occurs via a Ca²⁺-sensitive mechanism and that exogenous Ca²⁺ promotes lamin degradation in isolated thymocyte nuclei from untreated cells. Here we demonstrate that peptide-based inhibitors of the interleukin 1-converting enzyme family of cysteine proteases (Tyr-Val-Ala-Asp fluoromethyl ketone) and of the nuclear scaffold multicatalytic proteinase (Ala-Pro-Phe chloromethyl ketone) block the degradation of lamin B₁ to a 21-kDa fragment in thymocytes treated with glucocorticoid, the Ca²⁺-mobilizing agent thapsigargin, or antibodies to the T cell receptor. However, among a panel of inhibitors specific for several different proteases implicated in apoptosis, only tosylphenylalanyl chloromethyl ketone and the nuclear scaffold protease inhibitor block lamin degradation, histone H1 cleavage, and DNA fragmentation in isolated thymocyte nuclei incubated with Ca²⁺. Overexpression of human BCL-2 in nuclei by stable transfection resulted in an inhibition of Ca²⁺-stimulated lamin degradation and DNA fragmentation, suggesting that endogenous nuclear BCL-2 regulates activation of the nuclear scaffold protease. The results demonstrate the existence of an alternative pathway of lamin degradation and DNA fragmentation mediated by a resident Ca²⁺-stimulated nuclear protease that is not directly dependent upon activation of the interleukin 1-converting enzyme family of cell death regulators.

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