Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: up-regulation of cIAP2 by granulocyte colony-stimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia.

Abstract	Human neutrophils were found to express members of the inhibitor of apoptosis (IAP) family, namely cellular IAP1 (cIAP1), cIAP2, and X-linked IAP. Among these members, cIAP2 expression was selectively up-regulated by stimulation with granulocyte colony-stimulating factor (G-CSF), but not with granulocyte-macrophage CSF. The increased expression of cIAP2 mRNA was detected as early as 30 minutes after in vitro stimulation with G-CSF, and the elevated level of cIAP2 protein was detected at 1 hour. The elevated level of cIAP2 protein was also detected in peripheral blood neutrophils obtained from healthy donors receiving G-CSF administration. G-CSF-induced up-regulation of cIAP2 mRNA and protein, phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the antiapoptotic effects were inhibited by pretreatment of cells with AG490, a specific inhibitor of Janus kinase 2 (JAK2). Mature neutrophils from a patient with chronic neutrophilic leukemia exhibited remarkable overexpression of cIAP2 mRNA and prolongation of survival, whereas cIAP2 mRNA expression and survival in mature neutrophils from patients with chronic myelogenous leukemia were essentially similar to those in normal neutrophils. These findings suggest that cIAP2 expression is up-regulated by G-CSF through activation of the JAK2-STAT3 pathway, and increased expression of cIAP2 protein may contribute to G-CSF-mediated antiapoptosis. In addition, overexpression of cIAP2 may be partly responsible for sustained neutrophilia at least in some cases of chronic neutrophilic leukemia.
Authors	Taro Hasegawa, Kenichi Suzuki, Chikahiko Sakamoto, Kensuke Ohta, Saori Nishiki, Masayuki Hino, Noriyuki Tatsumi, Seiichi Kitagawa
Journal	Blood (Blood) Vol. 101 Issue 3 Pg. 1164-71 (Feb 01 2003) ISSN: 0006-4971 [Print] United States
PMID	12393423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	DNA-Binding Proteins Inhibitor of Apoptosis Proteins Insect Proteins Proteins Proto-Oncogene Proteins RNA, Messenger STAT3 Transcription Factor STAT3 protein, human Trans-Activators Granulocyte Colony-Stimulating Factor BIRC2 protein, human Ubiquitin-Protein Ligases Protein-Tyrosine Kinases JAK2 protein, human Janus Kinase 2
Topics	Apoptosis (drug effects) Case-Control Studies DNA-Binding Proteins (metabolism) Granulocyte Colony-Stimulating Factor (administration & dosage, pharmacology) Humans Inhibitor of Apoptosis Proteins Insect Proteins (biosynthesis, genetics) Janus Kinase 2 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Neutrophilic, Chronic (etiology, metabolism) Male Middle Aged Neutrophils (metabolism) Protein Biosynthesis Protein-Tyrosine Kinases (metabolism) Proteins (genetics) Proto-Oncogene Proteins RNA, Messenger (biosynthesis) STAT3 Transcription Factor Trans-Activators (metabolism) Ubiquitin-Protein Ligases Up-Regulation (drug effects)

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