|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 281, Issue 16, 10745-10751, April 21, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Increased CCAAT Enhancer-binding Protein 
(C/EBP) Expression and Premature Apoptosis in Myeloid Cells Expressing Gfi-1 N382S Mutant Associated with Severe Congenital Neutropenia*
1
From the
Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and the Comprehensive Cancer Center and Department of Laboratory Medicine, University of California, San Francisco, California 94143
Granulocyte-colony-stimulating factor (G-CSF) stimulates the activation of multiple signaling pathways, leading to alterations in the activities of transcription factors. Gfi-1 is a zinc finger transcriptional repressor that is required for granulopoiesis. How Gfi-1 acts in myeloid cells is poorly understood. We show here that the expression of Gfi-1 was up-regulated during G-CSF-induced granulocytic differentiation in myeloid 32D cells. Truncation of the carboxyl terminus of the G-CSF receptor, as seen in patients with acute myeloid leukemia evolving from severe congenital neutropenia, disrupted Gfi-1 up-regulation by G-CSF. Ectopic expression of a dominant negative Gfi-1 mutant, N382S, which was associated with severe congenital neutropenia, resulted in premature apoptosis and reduced proliferation of cells induced to differentiate with G-CSF. The expression of neutrophil elastase (NE) and CCAAT enhancer-binding protein 
(C/EBP) was significantly increased in 32D cells expressing N382S. In contrast, overexpression of wild type Gfi-1 abolished G-CSF-induced up-regulation of C/EBP but had no apparent effect on NE up-regulation by G-CSF. Notably, G-CSF-dependent proliferation and survival were inhibited upon overexpression of C/EBP but not NE. These data indicate that Gfi-1 down-regulates C/EBP expression and suggest that increased expression of C/EBP as a consequence of loss of Gfi-1 function may be deleterious to the proliferation and survival of early myeloid cells.
Received for publication, October 6, 2005 , and in revised form, February 15, 2006.
* This work was supported by Grant RO1CA92172 (to F. D.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Biological Sciences, University of Toledo, 2801 West Bancroft St., Toledo, OH 43606. Tel.: 419-530-1577; Fax: 419-530-7737; E-mail: fdong{at}utnet.utoledo.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Basu, Q. Liu, Y. Qiu, and F. Dong Gfi-1 represses CDKN2B encoding p15INK4B through interaction with Miz-1 PNAS, February 3, 2009; 106(5): 1433 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Berliner Lessons from congenital neutropenia: 50 years of progress in understanding myelopoiesis Blood, June 15, 2008; 111(12): 5427 - 5432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Yang, L. Wang, T. A. Kalfa, J. A. Cancelas, X. Shang, S. Pushkaran, J. Mo, D. A. Williams, and Y. Zheng Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis Blood, December 1, 2007; 110(12): 3853 - 3861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. De La Luz Sierra, P. Gasperini, P. J. McCormick, J. Zhu, and G. Tosato Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells Blood, October 1, 2007; 110(7): 2276 - 2285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khanna-Gupta, H. Sun, T. Zibello, H. M. Lee, R. Dahl, L. A. Boxer, and N. Berliner Growth factor independence-1 (Gfi-1) plays a role in mediating specific granule deficiency (SGD) in a patient lacking a gene-inactivating mutation in the C/EBP{epsilon} gene Blood, May 15, 2007; 109(10): 4181 - 4190. [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]
|
|
|
|
 |
|
 P. E. Newburger Disorders of Neutrophil Number and Function Hematology, January 1, 2006; 2006(1): 104 - 110. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |