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

• DOI: 10.1016/j.leukres.2012.08.024
• Publication Date: 2012-09-13T19:48:31Z
• Authors: Magali Humbert; Chantal Mueller; Martin F. Fey; Mario P. Tschan
• Keywords: 0303 health sciences; Neutrophils; Tumor Suppressor Proteins; Membrane Proteins; Nuclear Proteins; Proteins; Cell Differentiation; Tretinoin; Tumor Protein p73; 3. Good health; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Leukemia, Promyelocytic, Acute; Drug Resistance, Neoplasm; Cell Line, Tumor; Autophagy; Humans; Protein Isoforms; Gene Silencing; RNA, Small Interfering; Granulocytes; Signal Transduction

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.