Document Detail


Increased c-Jun expression and reduced GATA2 expression promote aberrant monocytic differentiation induced by activating PTPN11 mutants.
MedLine Citation:
PMID:  19528235     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Juvenile myelomonocytic leukemia (JMML) is characterized by myelomonocytic cell overproduction and commonly bears activating mutations in PTPN11. Murine hematopoietic progenitors expressing activating Shp2 undergo myelomonocytic differentiation, despite being subjected to conditions that normally support only mast cells. Evaluation of hematopoietic-specific transcription factor expression indicates reduced GATA2 and elevated c-Jun in mutant Shp2-expressing progenitors. We hypothesized that mutant Shp2-induced Ras hyperactivation promotes c-Jun phosphorylation and constitutive c-Jun expression, permitting, as a coactivator of PU.1, excessive monocytic differentiation and reduced GATA2. Hematopoietic progenitors expressing activating Shp2 demonstrate enhanced macrophage CFU (CFU-M) compared to that of wild-type Shp2-expressing cells. Treatment with the JNK inhibitor SP600125 or cotransduction with GATA2 normalizes activating Shp2-generated CFU-M. However, cotransduction of DeltaGATA2 (lacking the C-terminal zinc finger, needed to bind PU.1) fails to normalize CFU-M. NIH 3T3 cells expressing Shp2E76K produce higher levels of luciferase expression directed by the macrophage colony-stimulating factor receptor (MCSFR) promoter, which utilizes c-Jun as a coactivator of PU.1. Coimmunoprecipitation demonstrates increased c-Jun-PU.1 complexes in mutant Shp2-expressing hematopoietic progenitors, while chromatin immunoprecipitation demonstrates increased c-Jun binding to the c-Jun promoter and an increased c-Jun-PU.1 complex at the Mcsfr promoter. Furthermore, JMML progenitors express higher levels of c-JUN than healthy controls, substantiating the disease relevance of these mechanistic findings.
Authors:
Zhenyun Yang; Takako Kondo; Cara S Voorhorst; Sarah C Nabinger; Leila Ndong; Fuqin Yin; Edward M Chan; Menggang Yu; Oliver Würstlin; Christian P Kratz; Charlotte M Niemeyer; Christian Flotho; Eri Hashino; Rebecca J Chan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-06-15
Journal Detail:
Title:  Molecular and cellular biology     Volume:  29     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-07-27     Completed Date:  2009-09-09     Revised Date:  2010-09-27    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4376-93     Citation Subset:  IM    
Affiliation:
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anthracenes / metabolism
Cell Differentiation / physiology*
Child
Enzyme Activation
GATA2 Transcription Factor / genetics,  metabolism*
Gene Expression Regulation
Hematopoietic Stem Cells / cytology,  physiology
Humans
Infant
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors,  genetics,  metabolism*
Leukemia, Myelomonocytic, Juvenile / genetics
Mast Cells / cytology,  physiology
Mice
Monocytes / cytology,  physiology*
Mutation*
NIH 3T3 Cells
Promoter Regions, Genetic
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics,  metabolism*
Receptor, Macrophage Colony-Stimulating Factor / genetics,  metabolism
ras Proteins / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
R01DC007390/DC/NIDCD NIH HHS; R01HL082981/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anthracenes; 0/GATA2 Transcription Factor; 0/Gata2 protein, mouse; 0/anthra(1,9-cd)pyrazol-6(2H)-one; EC 2.7.10.1/Receptor, Macrophage Colony-Stimulating Factor; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11; EC 3.6.5.2/ras Proteins
Comments/Corrections

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