Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML. Leukemia 2010 May;24(5):914-23
Date
04/09/2010Pubmed ID
20376080Pubmed Central ID
PMC2923485DOI
10.1038/leu.2010.37Scopus ID
2-s2.0-77952423398 (requires institutional sign-in at Scopus site) 47 CitationsAbstract
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.
Author List
Pulikkan JA, Dengler V, Peer Zada AA, Kawasaki A, Geletu M, Pasalic Z, Bohlander SK, Ryo A, Tenen DG, Behre GAuthor
John A. Pulikkan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Biomarkers, TumorBlotting, Western
CCAAT-Enhancer-Binding Protein-alpha
Cell Differentiation
Chromatin Immunoprecipitation
Flow Cytometry
Gene Expression Profiling
Granulocytes
Humans
JNK Mitogen-Activated Protein Kinases
K562 Cells
Leukemia, Myeloid, Acute
Mutation
NIMA-Interacting Peptidylprolyl Isomerase
Oligonucleotide Array Sequence Analysis
Peptidylprolyl Isomerase
Promoter Regions, Genetic
Proteomics
RNA, Messenger
RNA, Small Interfering
Reverse Transcriptase Polymerase Chain Reaction
Ubiquitin