title: PKA/Smurf1 signaling-mediated stabilization of Nur77 is required for anticancer drug cisplatin-induced apoptosis.
abstract: The orphan nuclear receptor Nur77 regulates diverse cellular activities, including cell proliferation, differentiation and apoptosis. The c-Jun N-terminal kinase (JNK) have a dual role in controlling the function of Nur77. While JNK-mediated phosphorylation of Nur77 positively regulates its translocation to the mitochondria to induce apoptosis, it negatively regulates the stability of Nur77. The underlying mechanism for the dual role of JNK in regulating Nur77, however, is unclear. Here, we report that E3 ubiquitin ligase Smad ubiquitination regulatory factor 1 (Smurf1) prevents Nur77 degradation through mediating its unconventional ubiquitination, thereby mitigating the JNK-mediated downregulating effect, which leads to Nur77 accumulation and subsequent translocation to mitochondria to trigger apoptosis. In this process, protein kinase A (PKA)-mediated phosphorylation of Smurf1 at Thr306 is a prerequisite step. Accordingly, cyclic AMP/PKA signaling switches the fate of Nur77 from degradation to triggering apoptosis in chemotherapy drug cisplatin-treated cells. Hence, our study revealed a novel mechanism, by which PKA/Smurf1 antagonizes the downregulating effect of JNK on Nur77, leading to the accumulation of Nur77 for apoptosis induction triggered by cisplatin.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Life Sciences Institute and College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: F
authors.initials: F
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: H-R
authors.initials: HR
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D017868:Cyclic AMP-Dependent Protein Kinases; D048670:MAP Kinase Kinase 4; D002945:Cisplatin