Elevated PIN1 expression by C/EBPα-p30 blocks C/EBPα-induced granulocytic differentiation through c-Jun in AML

Abstract

The transcription factor CCAAT enhancer-binding protein a (C/EBPa) has an important role in granulopoiesis. The tumor suppressor function of C/EBPa is shown by the findings that loss of expression or function of C/EBPa in leukemic blasts contributes to a block in myeloid cell differentiation and to leukemia. C/EBPa mutations are found in around 9% of acute myeloid leukemia (AML) patients. The mechanism by which the mutant form of C/EBPa (C/EBPa-p30) exerts a differentiation block is not well understood. By using a proteomic screen, we have recently reported PIN1 as a target of C/EBPa-p30 in AML.In the present study, we show that C/EBPa-p30 induces PIN1 expression. We observed elevated PIN1 expression in leukemic patient samples. Induction of C/EBPa-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/EBPa 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 cJun ubiquitination, and c-Jun blocks granulocyte differentiation mediated by C/EBPa. Our data suggest that the inhibition of PIN1 could be a potential strategy of treating AML patients with C/EBPa mutation.

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

“…While our peptide mapping clearly shows specific sites in both TRIB2 and C/EBPα responsible for the direct interaction, in the absence of crystal structure information we cannot predict further based on our data the reason why p30 is not targeted by TRIB2 for degradation. Our data does not discount a role for p30 in TRIB2 mediated AML; p30 presence may, for example, activate a unique set of genes, inhibit other C/EBPs or bind to a unique set of proteins distinct from C/EBPα p42 as previously reported (32,33). Indeed, U937 cells ligases including β-TrCP, COP1 and Smurf1 (36).…”

Up-regulation of Translation Eukaryotic Initiation Factor 4E in Nucleophosmin 1 Haploinsufficient Cells Results in Changes in CCAAT Enhancer-binding Protein α Activity

“…Expression levels have been normalized to that of ␤-actin and calculated using the ⌬⌬C T method. Fold change in expression has been calculated for each gene by assuming its expression in untransfected cells is equal to 1. example, it has recently been shown that p30 up-regulates the expression of Ubc9 (32), an E2-Sumo-conjugating protein, and PIN1, peptidyl-prolyl cis/trans-isomerase (33). The up-regulation of Ubc9 does not require binding of p30 to the promoter of this gene.…”

PI3-Kinase/p38 Kinase-Dependent E2F1 Activation Is Critical for Pin1 Induction in Tamoxifen-Resistant Breast Cancer Cells

“…Wulf et al showed that Pin1 transcription was triggered by oncogenic Neu/Ras signaling via E2F activation (Ryo et al, 2002). Although a recent study reported the mutant form (C/EBPα-p30) of the CCAAT enhancer-binding proteinα has a positive effect on Pin1 gene transcription in leukemia cells, C/EBPα-p30 indirectly stimulated Pin1 transcription via an increase in E2F1 recruitment in the gene promoter (Pulikkan et al, 2010).…”