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Death-associated protein 5 (DAP5/p97/NAT1) contributes to retinoic acid-induced granulocytic differentiation and arsenic trioxide-induced apoptosis in acute promyelocytic leukemia

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Abstract

All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells. Here we investigated the role and regulation of death-associated protein-5 (DAP5/p97/NAT1), a novel inhibitor of translational initiation, in APL cell differentiation and apoptosis. We found that ATRA markedly induced DAP5/p97 protein and gene expression and nuclear translocation during terminal differentiation of APL (NB4) and HL60 cells but not differentiation-resistant cells (NB4.R1 and HL60R), which express very low levels of DAP5/p97. At the differentiation inducing concentrations, ATO (<0.5 μM), dimethyl sulfoxide, 1,25-dihydroxy-vitamin-D3, and phorbol-12-myristate 13-acetate also significantly induced DAP5/p97 expression in NB4 cells. However, ATO administered at apoptotic doses (1–2 μM) induced expression of DAP5/p86, a proapoptotic derivative of DAP5/p97. ATRA and ATO-induced expression of DAP5/p97 was associated with inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Furthermore, DAP5/p97 expression was upregulated by inhibition of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway via LY294002 and via rapamycin. Finally, knockdown of DAP5/p97 expression by small interfering RNA inhibited ATRA-induced granulocytic differentiation and ATO-induced apoptosis. Together, our data reveal new roles for DAP5/p97 in ATRA-induced differentiation and ATO-induced apoptosis in APL and suggest a novel regulatory mechanism by which PI3K/Akt/mTOR pathway inhibition mediates ATRA- and ATO-induced expression of DAP5/p97.

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Abbreviations

AML:

Acute myeloid leukemia

APL:

Acute promyelocytic leukemia

ATO:

Arsenic trioxide

ATRA:

All-trans-retinoic acid

DAP5:

Death-associated protein 5

DMSO:

Dimethyl sulfoxide

eIF2:

Eukaryotic initiation factor 2

eIF4E:

Eukaryotic initiation factor 4E

FACS:

Fluorescence-activated cell sorting

FITC:

Fluorescein isothiocyanate

IRES:

Internal ribosome entry site

MTOR:

Mammalian target of rapamycin

PBS:

Phosphate-buffered saline

PDCD4:

Programmed cell death 4 protein

PI3K:

Phosphatidylinositol 3-kinase

PMA:

Phorbol-12-myristate 13-acetate

PML:

Promyelocytic leukemia

RARα:

Retinoic acid receptor-α

SiRNA:

Small interfering RNA

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Acknowledgments

We would like to thank Karen Ramires for help in conducting our FACS analyses, Kenneth Dunner Jr. in M. D. Anderson Cancer Center’s NCI-funded High Resolution Electron Microscopy Facility for his help in performing electron microscopy, and Pierrette Lo for editing the manuscript. Supported in part by National Cancer Institute grant U54 RFA CA096300.

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  1. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 422, Houston, TX, 77030, USA

    Bulent Ozpolat, Ugur Akar, Isabel Zorrilla-Calancha, Pablo Vivas-Mejia, Marian Acevedo-Alvarez & Gabriel Lopez-Berestein

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  1. Bulent Ozpolat
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  2. Ugur Akar
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  6. Gabriel Lopez-Berestein
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Correspondence to Gabriel Lopez-Berestein.

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B. Ozpolat and U. Akar contributed equally.

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Ozpolat, B., Akar, U., Zorrilla-Calancha, I. et al. Death-associated protein 5 (DAP5/p97/NAT1) contributes to retinoic acid-induced granulocytic differentiation and arsenic trioxide-induced apoptosis in acute promyelocytic leukemia. Apoptosis 13, 915–928 (2008). https://doi.org/10.1007/s10495-008-0222-9

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