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Molecular and Cellular Biology, May 2005, p. 3704-3714, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3704-3714.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Anja Krippner-Heidenreich,^1, Gesa Walsemann,^2, Maroun J. Beyrouthy,^3, Stefanie Speckgens,² Regine Kraft,⁴ Hubert Thole,⁵ Robert V. Talanian,⁶ Myra M. Hurt,³ and Bernhard Lüscher^2*

Institut für Zellbiologie und Immunologie, Universität Stuttgart, Stuttgart,¹ Abteilung Biochemie und Molekularbiologie, Institut für Biochemie, Universitätsklinikum der RWTH, Aachen,² Max-Delbrück-Centrum, Proteinchemie, Berlin,⁴ Solvay Pharmaceuticals Research Laboratories, Hannover, Germany,⁵ College of Medicine, Florida State University, Tallahassee, Florida,³ Department of Biochemistry, Abbott Bioresearch Center, Worcester, Massachusetts⁶

Received 20 August 2004/ Returned for modification 10 November 2004/ Accepted 7 February 2005

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 (YY1119) that has lost its transactivation domain but retains its DNA binding domain. Indeed, YY1119 is no longer able to stimulate gene transcription but interacts with DNA. YY1119 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.

A.K.-H., G.W., and M.J.B. contributed equally to this work.

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