SEARCH:   Advanced

Blood, 1 May 2005, Vol. 105, No. 9, pp. 3397-3404. Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI 10.1182/blood-2004-07-2618. This Article Full Text (PDF) All Versions of this Article: 2004-07-2618v1 105/9/3397    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Massullo, P. Articles by Avalos, B. R Search for Related Content PubMed PubMed Citation Articles by Massullo, P. Articles by Avalos, B. R Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 13, 2004 Accepted December 27, 2004 Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes Pam Massullo, Lawrence J Druhan, Bruce A Bunnell, Melissa G Hunter, John M Robinson, Clay B Marsh, and Belinda R Avalos* The Bone Marrow Transplant Program, The Ohio State University, Columbus, OH, USA The Division of Hematology/Oncology, The Ohio State University, Columbus, OH, USA The Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH, USA Department of Pharmacology, Center for Gene Therapy, Tulane University Health Science Center, New Orleans, LA, USA Division of Pulmonary and Critical Care Medicine, The Ohio State University, Columbus, OH, USA Department of Physiology, The Ohio State University, Columbus, OH, USA * Corresponding author; email: avalos-1{at}medctr.osu.edu. Mutations in the ELA2 gene encoding neutrophil elastase (NE) are present in the majority of patients with severe congenital neutropenia (SCN). However, the mechanisms by which these mutations cause neutropenia remain unknown. To investigate the effects of expression of mutant NE on granulopoiesis, we used the HL-60 promyelocytic cell line retrovirally transduced with the G185R NE mutant that is associated with a severe SCN phenotype. We show that the mutant enzyme accelerates apoptosis of differentiating but not proliferating cells. Using metabolic labeling, confocal immunofluorescence microscopy, and immunoblot analysis of subcellular fractions, we also demonstrate that the G185R mutant is abnormally processed and localizes predominantly to the nuclear and plasma membranes instead of the cytoplasmic compartment observed with the wild-type (WT) enzyme. Expression of the G185R mutant appeared to alter the subcellular distribution and expression of adaptor protein 3 (AP3), which traffics proteins from the trans-Golgi to the endosome. These observations provide further insights into potential mechanisms by which NE mutations cause neutropenia and suggest that abnormal protein trafficking and accelerated apoptosis of differentiating myeloid cells contribute to the severe SCN phenotype resulting from the G185R mutation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Neutrophil elastase unleashed Marshall Horwitz Blood 2005 105: 3392-3393. [Full Text] [PDF] This article has been cited by other articles: P. Rujkijyanont, K.-i. Watanabe, C. Ambekar, H. Wang, A. Schimmer, J. Beyene, and Y. Dror SBDS-deficient cells undergo accelerated apoptosis through the Fas-pathway Haematologica, March 1, 2008; 93(3): 363 - 371. [Abstract] [Full Text] [PDF] D. S. Grenda, M. Murakami, J. Ghatak, J. Xia, L. A. Boxer, D. Dale, M. C. Dinauer, and D. C. Link Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis Blood, December 15, 2007; 110(13): 4179 - 4187. [Abstract] [Full Text] [PDF] M. Donini, S. Fontana, G. Savoldi, W. Vermi, L. Tassone, F. Gentili, E. Zenaro, D. Ferrari, L. D. Notarangelo, F. Porta, et al. G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms Blood, June 1, 2007; 109(11): 4716 - 4723. [Abstract] [Full Text] [PDF] C. U. Niemann, M. Abrink, G. Pejler, R. L. Fischer, E. I. Christensen, S. D. Knight, and N. Borregaard Neutrophil elastase depends on serglycin proteoglycan for localization in granules Blood, May 15, 2007; 109(10): 4478 - 4486. [Abstract] [Full Text] [PDF] M. S. Horwitz, Z. Duan, B. Korkmaz, H.-H. Lee, M. E. Mealiffe, and S. J. Salipante Neutrophil elastase in cyclic and severe congenital neutropenia Blood, March 1, 2007; 109(5): 1817 - 1824. [Abstract] [Full Text] [PDF] I. Kollner, B. Sodeik, S. Schreek, H. Heyn, N. von Neuhoff, M. Germeshausen, C. Zeidler, M. Kruger, B. Schlegelberger, K. Welte, et al. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response Blood, July 15, 2006; 108(2): 493 - 500. [Abstract] [Full Text] [PDF] A. Enders, B. Zieger, K. Schwarz, A. Yoshimi, C. Speckmann, E.-M. Knoepfle, U. Kontny, C. Muller, A. Nurden, J. Rohr, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II Blood, July 1, 2006; 108(1): 81 - 87. [Abstract] [Full Text] [PDF] D. Zhuang, Y. Qiu, S. C. Kogan, and F. Dong Increased CCAAT Enhancer-binding Protein {epsilon} (C/EBP{epsilon}) Expression and Premature Apoptosis in Myeloid Cells Expressing Gfi-1 N382S Mutant Associated with Severe Congenital Neutropenia J. Biol. Chem., April 21, 2006; 281(16): 10745 - 10751. [Abstract] [Full Text] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020