Inhibition of damage-regulated autophagy modulator-1 (DRAM-1) impairs neutrophil differentiation of NB4 APL cells

Magali Humbert; Chantal Mueller; Martin F Fey; Mario P Tschan

doi:10.1016/j.leukres.2012.08.024

Inhibition of damage-regulated autophagy modulator-1 (DRAM-1) impairs neutrophil differentiation of NB4 APL cells

Leuk Res. 2012 Dec;36(12):1552-6. doi: 10.1016/j.leukres.2012.08.024. Epub 2012 Sep 13.

Authors

Magali Humbert¹, Chantal Mueller, Martin F Fey, Mario P Tschan

Affiliation

¹ Experimental Oncology/Hematology, Department of Clinical Research, University of Bern, Bern, Switzerland.

PMID: 22981223
DOI: 10.1016/j.leukres.2012.08.024

Abstract

The damage-regulator autophagy modulator 1 (DRAM-1) is a lysosomal protein that positively regulates autophagy in a p53-dependent manner. We aimed at analyzing the role of DRAM-1 in granulocytic differentiation of APL cells. We observed a significant increase of DRAM-1 expression during all-trans retinoic acid (ATRA)-induced neutrophil differentiation of NB4 APL cells but not in ATRA-resistant NB4-R2 cells. Next, knocking down DRAM-1 in NB4 APL cells was sufficient to impair neutrophil differentiation. Given that DRAM-1 is a transcriptional target of p53, we tested if DRAM-1 is regulated by the p53 relative p73. Indeed, inhibiting p73 prevented neutrophil differentiation and DRAM-1 induction of NB4 cells. In conclusion, we show for the first time that p73-regulated DRAM-1 is functionally involved in neutrophil differentiation of APL cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Cell Differentiation
Cell Line, Tumor
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Gene Silencing
Granulocytes / pathology
Humans
Leukemia, Promyelocytic, Acute / pathology*
Membrane Proteins
Neutrophils / drug effects
Neutrophils / metabolism*
Neutrophils / pathology
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / genetics
Protein Isoforms / metabolism
Proteins / antagonists & inhibitors
Proteins / genetics*
Proteins / metabolism
RNA, Small Interfering / genetics
Signal Transduction
Tretinoin / pharmacology
Tumor Protein p73
Tumor Suppressor Proteins / antagonists & inhibitors
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism

Substances

DNA-Binding Proteins
DRAM1 protein, human
Membrane Proteins
Nuclear Proteins
Protein Isoforms
Proteins
RNA, Small Interfering
TP73 protein, human
Tumor Protein p73
Tumor Suppressor Proteins
Tretinoin