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A more recent version of this article appeared on June 1, 2004
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Submitted on August 25, 2003
Revised on February 18, 2004
Accepted on March 22, 2004
1 Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia - Università di Udine. P.le Kolbe 4 - 33100 Udine ITALY; MATI Center of Excellence - Università di Udine. P.le Kolbe 4 - 33100 Udine ITALY
2 Laboratorio Nazionale CIB -Area Science Park- Padriciano 99 Trieste ITALY
3 Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia - Università di Udine. P.le Kolbe 4 - 33100 Udine ITALY; Laboratorio Nazionale CIB -Area Science Park- Padriciano 99 Trieste ITALY
* Corresponding author. E-mail address: cbrancolini{at}makek.dstb.uniud.it.
HDACs are important regulators of gene expression as part of transcriptional corepressor complexes. Here we demonstrate that caspases can repress the activity of the MEF2C transcription factor by regulating HDAC4 processing. Cleavage of HDAC4 occurs at Asp 289 and disjoins the carboxy-terminal fragment, localized into the cytoplasm, from the amino-terminal fragment, which accumulates into the nucleus. In the nucleus, the caspase-generated fragment of HDAC4 is able to trigger cytochrome c release from mitochondria and cell death in a caspase-9 dependent manner. The caspase-cleaved amino-terminal fragment of HDAC4 acts as a strong repressor of the transcription factor MEF2C, independently from the HDAC domain. Removal of aminoacids 166-289 from the caspase-cleaved fragment of HDAC4 abrogates its ability to repress MEF2 transcription and to induce cell death. Caspase-2 and caspase-3 cleave HDAC4 in vitro and caspase-3 is critical for HDAC4 cleavage in vivo during UV-induced apoptosis. After UV irradiation GFP-HDAC4 translocates into the nucleus coincidentally/immediately before the retraction response, but clearly before nuclear fragmentation. Altogether our studies indicate that caspases could specifically modulate gene repression and apoptosis through the proteolyic processing of HDAC4.
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