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Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML.
- Source :
- Leukemia (08876924); May2010, Vol. 24 Issue 5, p914-923, 10p, 1 Diagram, 5 Graphs
- Publication Year :
- 2010
-
Abstract
- The transcription factor CCAAT enhancer-binding protein alpha (C/EBPalpha) has an important role in granulopoiesis. The tumor suppressor function of C/EBPalpha is shown by the findings that loss of expression or function of C/EBPalpha in leukemic blasts contributes to a block in myeloid cell differentiation and to leukemia. C/EBPalpha mutations are found in around 9% of acute myeloid leukemia (AML) patients. The mechanism by which the mutant form of C/EBPalpha (C/EBPalpha-p30) exerts a differentiation block is not well understood. By using a proteomic screen, we have recently reported PIN1 as a target of C/EBPalpha-p30 in AML. In the present study, we show that C/EBPalpha-p30 induces PIN1 expression. We observed elevated PIN1 expression in leukemic patient samples. Induction of C/EBPalpha-p30 results in recruitment of E2F1 in the PIN1 promoter. We show that the inhibition of PIN1 leads to myeloid differentiation in primary AML blasts with C/EBPalpha mutations. Overexpression of PIN1 in myeloid cells leads to block of granulocyte differentiation. We also show that PIN1 increases the stability of the c-Jun protein by inhibiting c-Jun ubiquitination, and c-Jun blocks granulocyte differentiation mediated by C/EBPalpha. Our data suggest that the inhibition of PIN1 could be a potential strategy of treating AML patients with C/EBPalpha mutation. [ABSTRACT FROM AUTHOR]
- Subjects :
- PROTEIN binding
TUMOR suppressor proteins
ACUTE myeloid leukemia
GENETIC mutation
GRANULOCYTES
ENZYME inhibitors
PROTEIN metabolism
RNA metabolism
ENZYME metabolism
CELL differentiation
CELLS
COMPARATIVE studies
ENZYMES
FLOW cytometry
GENES
RESEARCH methodology
MEDICAL cooperation
POLYMERASE chain reaction
PROTEINS
RESEARCH
RESEARCH funding
RNA
TRANSFERASES
WESTERN immunoblotting
PROTEOMICS
EVALUATION research
REVERSE transcriptase polymerase chain reaction
OLIGONUCLEOTIDE arrays
GENE expression profiling
Subjects
Details
- Language :
- English
- ISSN :
- 08876924
- Volume :
- 24
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- Leukemia (08876924)
- Publication Type :
- Academic Journal
- Accession number :
- 50393795
- Full Text :
- https://doi.org/10.1038/leu.2010.37