Activation of G0S2 is coordinated by recruitment of PML/RARα and C/EBPɛ to its promoter during ATRA-induced APL differentiation

Autor: Jiang Zhu, Ji Zhang, Wang Long Deng, Yong Lan Zhu, Fang Zhang
Rok vydání: 2016
Předmět:
Zdroj: Journal of Leukocyte Biology. 101:655-664
ISSN: 1938-3673
0741-5400
DOI: 10.1189/jlb.1a0316-116r
Popis: All-trans retinoic acid (ATRA) binds the promyelocytic leukemia/retinoic acid receptor α (PML/RARα) fusion protein and is an effective oncogene-targeted therapy for acute promyelocytic leukemia (APL). However, the molecular basis of PML/RARα-mediated transcriptional control during ATRA-induced differentiation is unclear. Previous studies have shown that the PML/RARα fusion protein behaves as a type II nuclear receptor, binding to DNA regardless of ligand status. Here, we performed a series of chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) experiments, demonstrating that there is an additional mode of action of PML/RARα, wherein PML/RARα does not bind DNA in the absence of ATRA but binds DNA and activates adjacent genes in the presence of ATRA. This mode of action is similar to that of a type I nuclear receptor and is highlighted by activation of G0/G1 switch gene 2 (G0S2) during ATRA-induced neutrophil differentiation of leukemia cell lines (NB4 and PR9) and primary human APL cells. C/EBPɛ occupancy of the G0S2 promoter was elevated in parallel with recruitment of PML/RARα in ATRA-treated NB4, PR9, and primary APL cells. Furthermore, we verified that the p30 isoform of C/EBPɛ is crucial for activation of G0S2 and that PML/RARα interacts physically and cooperates functionally with C/EBPɛ to up-regulate G0S2. Our data not only demonstrate a new mode of action of PML/RARα but also suggest a novel model in which PML/RARα synergizes with C/EBPɛ to reactivate the C/EBPɛ target G0S2, thereby contributing to ATRA-mediated APL differentiation and potentially, clinical remission.
Databáze: OpenAIRE