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Blood, 1 October 2004, Vol. 104, No. 7, pp. 2035-2043.
Prepublished online as a Blood First Edition Paper on June 8, 2004; DOI 10.1182/blood-2004-01-0065.
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Submitted January 8, 2004
Accepted May 26, 2004
Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal mediated event
Stephanie Plenchette, Severine Cathelin, Cedric Rebe, Sophie Launay, Sylvain Ladoire, Olivier Sordet, Tibor Ponnelle, Najet Debili, Thi Hai Phan, Rose-Ann Padua, Laurence Dubrez-Daloz, and Eric Solary*
IFR100, Faculty of Medicine, INSERM U517,, Dijon, France
IFR100, Faculty of Medicine, INSERM EPI 106, Dijon, France
Institut Gustave Roussy, INSERM U362, Villejuif, France
Institut Universitaire d'hematologie, Hopital Saint-Louis, INSERM EMI 3, Paris, France
Institut Universitaire d'hematologie, Hopital Saint-Louis, INSERM EMI 3, Paris, France; King's College Hospital, Rayne Institute, London, United Kingdom
* Corresponding author; email: esolary{at}u-bourgogne.fr.
The caspase inhibitor and RING finger-containing protein c-IAP1 has been shown to be involved in both apoptosis inhibition and signaling by members of the TNF-receptor family. The protein is regulated transcriptionally, e.g. is a target for NF- B, and can be inhibited by mitochondrial proteins released in the cytoplasm upon apoptotic stimuli. The present study indicates that an additional level of regulation of c-IAP1 may be cell compartmentalization. The protein is present in the nucleus of undifferentiated U937 and THP1 monocytic cell lines. When these cells undergo differentiation under phorbol ester exposure, c-IAP1 translocates to the cytoplasmic side of the Golgi apparatus. This redistribution involves a nuclear-export signal (NES)-mediated, leptomycin B-sensitive mechanism. Using site-directed mutagenesis, we localized the functional NES motif in the CARD domain of c-IAP1. A nucleo-cytoplasmic redistribution of the protein was also observed in human monocytes as well as in tumor cells from epithelial origin when undergoing differentiation. c-IAP1 does not translocate from the nucleus of cells whose differentiation is blocked, i.e. in cell lines and monocytes from transgenic mice overexpressing Bcl-2 and in monocytes from patients with chronic myelomonocytic leukemia. Altogether, these observations associate c-IAP1 cellular location with cell differentiation, which opens new perspectives on the functions of the protein.
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