Distinct TP73-DAPK2-ATG5 pathway involvement in ATO-mediated cell death versus ATRA-mediated autophagy responses in APL.

Humbert, Magali; Federzoni, Elena; Tschan, Mario (2017). Distinct TP73-DAPK2-ATG5 pathway involvement in ATO-mediated cell death versus ATRA-mediated autophagy responses in APL. Journal of leukocyte biology, 102(6), pp. 1357-1370. Society for Leukocyte Biology 10.1189/jlb.1A0317-132R

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We have previously demonstrated that the death-associated protein kinase 2 (DAPK2) expression is significantly reduced in acute myeloid leukemia (AML), particularly in acute promyelocytic leukemia (APL) blast cells. In this study, we aimed at further understanding DAPK2 function and regulation during arsenic trioxide (ATO) cytotoxic or all-trans retinoic acid (ATRA) differentiation therapy in APL cells. We found that the p53 family member transactivation domain-p73 isoform (TAp73) binds to and activates the DAPK2 promoter, whereas the dominant-negative ΔNp73 isoform inhibits DAPK2 transcription. Furthermore, the knocking down of tumor protein p73 (TP73) in NB4 cells resulted in reduced DAPK2 expression associated with decreased cell death and autophagy upon ATO and ATRA treatment, respectively. Moreover, the silencing of DAPK2 revealed that DAPK2 is an important downstream effector of p73 in ATO-induced apoptosis but not autophagy responses of APL cells. In contrast, the p73-DAPK2 pathway is essential for ATRA-induced autophagy that is mediated by an interaction of DAPK2 with the key autophagy-related protein (ATG)5. Lastly, we show that DAPK2 binds and stabilizes the p73 protein; thus, we propose a novel mechanism by which ATO- or ATRA-induced therapy responses initiate a positive p73-DAPK2 feedback loop.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Humbert, Magali; Federzoni, Elena and Tschan, Mario

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0741-5400

Publisher:

Society for Leukocyte Biology

Language:

English

Submitter:

Mario Tschan

Date Deposited:

09 Oct 2017 17:21

Last Modified:

03 Dec 2017 01:31

Publisher DOI:

10.1189/jlb.1A0317-132R

PubMed ID:

28978663

Uncontrolled Keywords:

DRP-1 apoptosis p73, AML

URI:

https://boris.unibe.ch/id/eprint/106027

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