Caspase-Dependent Regulation and Subcellular Redistribution of the Transcriptional Modulator YY1 during Apoptosis

Abstract

The transcriptional regulator Yin Yang 1 (YY1) controls many aspects of cell behavior and is essential for development. We analyzed the fate of YY1 during apoptosis and studied the functional consequences. We observed that this factor is rapidly translocated into the cell nucleus in response to various apoptotic stimuli, including activation of Fas, stimulation by tumor necrosis factor, and staurosporine and etoposide treatment. Furthermore, YY1 is cleaved by caspases in vitro and in vivo at two distinct sites, IATD₁₂G and DDSD₁₁₉G, resulting in the deletion of the first 119 amino acids early in the apoptotic process. This activity generates an N-terminally truncated YY1 fragment (YY1Δ119) that has lost its transactivation domain but retains its DNA binding domain. Indeed, YY1Δ119 is no longer able to stimulate gene transcription but interacts with DNA. YY1Δ119 but not the wild-type protein or the caspase-resistant mutant YY1D12A/D119A enhances Fas-induced apoptosis, suggesting that YY1 is involved in a positive feedback loop during apoptosis. Our findings provide evidence for a new mode of regulation of YY1 and define a novel aspect of the involvement of YY1 in the apoptotic process.

ACKNOWLEDGMENTS

We thank P. Hurlin, D. Litchfield, and J. Tschopp for reagents and Beth Alexander, Sabine Schreek, Jürgen Stahl, Sylvia Willi, and Gudrun Zimmermann for expert technical assistance.

This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (LU 466/1) to B.L.