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.
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.
Plenchette
Stéphanie
S
Institut National de la Sante et de la Recherche Médicale U517, INSERM EPI 106, IFR100, Dijon, France.
Cathelin
Séverine
S
Rébé
Cédric
C
Launay
Sophie
S
Ladoire
Sylvain
S
Sordet
Olivier
O
Ponnelle
Tibor
T
Debili
Najet
N
Phan
Thi-Hai
TH
Padua
Rose-Ann
RA
Dubrez-Daloz
Laurence
L
Solary
Eric
E
D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D006056:Golgi Apparatus / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007930:Leucine / Q000737:chemistry; D008164:Luminescent Proteins / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D014357:Trypsin / Q000494:pharmacology; D020298:U937 Cells; D044767:Ubiquitin-Protein Ligases
D051034:Inhibitor of Apoptosis Proteins; D008164:Luminescent Proteins; D016328:NF-kappa B; D011506:Proteins; D049452:Green Fluorescent Proteins; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; D014357:Trypsin; D007930:Leucine