Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia

Abstract

All-trans-retinoic acid (ATRA) induces growth inhibition, differentiation, and apoptosis in cancer cells, including acute promyelocytic leukemia (APL). In APL, expression of promyelocytic leukemia protein retinoic acid receptor-␣ (PML-RAR␣) fusion protein, owing to the t(15; 17) reciprocal translocation, leads to a block in the promyelocytic stage of differentiation. Here, we studied molecular mechanisms involved in ATRA-induced growth inhibition and myeloid cell differentiation in APL. By employing comprehensive high-throughput proteomic methods of 2-dimensional (2-D) gel electrophoresis and amino acid-coded mass tagging coupled with electrospray ionization (ESI) mass spectrometry, we systematically identified a total of 59 differentially expressed proteins that were consistently modulated in response to ATRA treatment. The data revealed significant downregulation of eukaryotic initiation and elongation factors, initiation factor 2 (IF2), eukaryotic initiation factor 4AI (eIF4AI), eIF4G, eIF5, eIF6, eukaryotic elongation factor 1A-1 (eEF1A-1), EF-1-␦, eEF1␥, 14-3-3⑀, and 14-3-3/␦ (P < .05). The translational inhibitor DAP5/p97/NAT1 (deathassociated protein 5) and PML isoform-1 were found to be up-regulated (P < .05). Additionally, the down-regulation of heterogeneous nuclear ribonucleoproteins (hnRNPs) C1/C2, UP2, K, and F; small nuclear RNPs (snRNPs) D3 and E; nucleoprotein tumor potentiating region (TPR); and protein phosphatase 2A (PP2A) were found (P < .05); these were found to function in pre-mRNA processing, splicing, and export events. Importantly, these pro-

Recent advances in blood‐related proteomics

“…This disease leads to the accumulation of pathological hematopoietic precursors in bone marrow. In this study, Harris et al [169] showed that all-trans-retinoic acid treatment of acute promyelocytic leukemia cells resulted in resetting the regulation of the posttranscriptional suppressive pathways. Fifty-nine differentially expressed proteins were pointed out, including eukaryotic initiation and elongation factors, heterogeneous nuclear ribonucleoproteins (RNPs), and small nuclear RNPs [169].…”

“…In this study, Harris et al [169] showed that all-trans-retinoic acid treatment of acute promyelocytic leukemia cells resulted in resetting the regulation of the posttranscriptional suppressive pathways. Fifty-nine differentially expressed proteins were pointed out, including eukaryotic initiation and elongation factors, heterogeneous nuclear ribonucleoproteins (RNPs), and small nuclear RNPs [169]. The response to p38 mitogen-activated protein kinase inhibitor SB203580 was evaluated in transformed follicular lymphoma cells by quantitative proteomic (ICAT-LC-MS/MS) and transcriptional (cDNA microarrays) analyses by Lin et al [170].…”

Comparative Proteomic Expression Profile in All-trans Retinoic Acid Differentiated Neuroblastoma Cell Line

“…Among these, the initiation factor IF-2, the elongation factors eEF-1gamma and eEF-1alpha1, the heterogeneous nuclear ribonucleoprotein hnRNP F, and the eukaryotic initiation factors eIF4A-1 and eIF4A-2 are known to be down-regulated by ATRA in acute promyelocytic cells. [27][28][29] In particular, IF-2, eEF-1gamma and eEF-1alpha1 have roles in the elongation stages of the protein synthesis mechanism, and hnRNP F, eIF4A-1 and eIF4A-2 have roles in mRNA processing and transport. This may suggest that ATRA-induced differentiation of NB could share these six effectors with ATRA-induced differentiation in PML cells.…”

“…Previously, 2D-PAGE analyses of protein changes were performed to study chemoresistance, 22 to search for markers for tumor diagnosis in NB cell lines, 23,24 and to study quantitatively and qualitatively differences in healthy and pathological NB mouse samples. 25,26 Moreover, proteomic characterization of differentiation induced by ATRA has been described in promyelocytic cells 7,27,28 and in mouse embryonic stem cells. 29 However, very little is known about the large-scale protein components of early stage differentiation of NB cell lines into neural cells by ATRA.…”

Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies

“…[68][69][70] In that way, in a recent study, 71 the protein profile of the AML subtypes has been analyzed, in an attempt to delineate the aberrant gene expression underlying the pathogenesis of this malignancy. The proteomic analysis, performed in blast from newly diagnosed acute myeloid leukemia patients, allowed to the identification of several proteins differentially expressed in the leukemia subtypes.…”