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

Plenchette S, Cathelin S, Rebe C, Launay S, Ladoire S, Sordet O, Ponnelle T, Debili N, Phan TH, Padua RA, Dubrez-Daloz L and Solary E
Source: Blood
Publication Date: (2004)
Issue: 104(7): 2035-2043
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
The caspase inhibitor and RING finger-containing protein cellular inhibitor of apoptosis protein 1 (c-IAP1) has been shown to be involved in both apoptosis inhibition and signaling by members of the tumor necrosis factor (TNF) receptor family. The protein is regulated transcriptionally (eg, is a target for nuclear factor-kappaB [NF-kappaB]) 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 caspase recruitment domain (CARD) of c-IAP1. A nucleocytoplasmic 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 (ie, in cell lines and monocytes from transgenic mice overexpressing B-cell lymphoma 2 [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.