Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML.
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.
Pulikkan
J A
JA
State Center for Cell and Gene Therapy, Department of Oncology and Hematology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Dengler
V
V
Peer Zada
A A
AA
Kawasaki
A
A
Geletu
M
M
Pasalic
Z
Z
Bohlander
S K
SK
Ryo
A
A
Tenen
D G
DG
Behre
G
G
D014408:Biomarkers, Tumor; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020411:Oligonucleotide Array Sequence Analysis; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism
D014408:Biomarkers, Tumor; D022763:CCAAT-Enhancer-Binding Protein-alpha; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025801:Ubiquitin; D048031:JNK Mitogen-Activated Protein Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase