title: Elevated c-Jun expression in acute myeloid leukemias inhibits C/EBPalpha DNA binding via leucine zipper domain interaction.
abstract: Transcription factor C/EBPalpha induces normal myeloid differentiation, inactivation of C/EBPalpha leads to a differentiation block in acute myeloid leukemias (AML), and overexpression of C/EBPalpha results in AML growth arrest and differentiation. Recent reports suggest that C/EBPalpha is activated or inactivated via protein-protein interactions. We previously reported that C/EBPalpha needs to inactivate the proto-oncogene c-Jun via leucine zipper domain interaction in order to induce granulocytic differentiation. We, therefore, hypothesized that c-Jun expression might be elevated in AML and subsequently inactivate C/EBPalpha. In fact, compared to normal bone marrow mononuclear cells, c-Jun expression is increased in AML patient samples (Affymetrix expression microarray analysis, n=166). c-Jun binds to C/EBPalpha via the leucine zipper domains and prevents C/EBPalpha from DNA binding. Inactivation of C/EBPalpha by c-Jun is necessary for c-Jun to induce proliferation because c-Jun-induced proliferation can be prevented by ectopic overexpression of C/EBPalpha. The dominant-negative 30-kDa C/EBPalpha protein, found in AML, fails to downregulate c-Jun mRNA expression in AML patient samples. Thus, our data suggest a model for AML in which c-Jun promotes proliferation and prevents differentiation by inhibiting C/EBPalpha DNA binding via leucine zipper domain interaction. It might depend on the expression levels of C/EBPalpha and c-Jun, if inhibition of C/EBPalpha by c-Jun or if inhibition of c-Jun by C/EBPalpha is more predominant: proliferation versus differentiation; AML versus normal myeloid development.
authors.affiliation: Medicine III at University of Munich Hospital Grosshadern and GSF Research Center, Munich, Germany.
authors.forename: Janki
authors.initials: J
authors.lastname: Rangatia
authors.forename: Rajani K
authors.initials: RK
authors.lastname: Vangala
authors.forename: Sheo M
authors.initials: SM
authors.lastname: Singh
authors.forename: Abdul A
authors.initials: AA
authors.lastname: Peer Zada
authors.forename: Annika
authors.initials: A
authors.lastname: Elsässer
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmann
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Behre
mesh_terms: D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation; D002455:Cell Division; D004247:DNA / Q000378:metabolism*; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D016350:Leucine Zippers; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000737:chemistry; D008958:Models, Molecular; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases