Abstract
Orphan nuclear receptor Nur77 promotes apoptosis by targeting mitochondria through interaction with Bcl-2, an event that converts Bcl-2 from a survival to killer. However, how the Nur77-Bcl-2 apoptotic pathway is regulated remains largely unknown. In this study, we examined the regulation of the Nur77-Bcl-2 pathway by CCE9, a xanthone compound. Our results demonstrated that the apoptotic effect of CCE9 depended on its induction of Nur77 expression, cytoplasmic localization, and mitochondrial targeting. The activation of the Nur77-Bcl-2 pathway by CCE9 was associated with its activation of p38α MAPK. Inhibition of p38α MAPK activation by knocking down or knocking out p38α MAPK impaired the effect of CCE9 on inducing apoptosis and the expression and cytoplasmic localization of Nur77. In addition, CCE9 activation of p38α MAPK resulted in Bcl-2 phosphorylation and Bcl-2 interaction with Nur77, whereas inhibition of p38α MAPK activation or expression suppressed the interaction. Moreover, mutating Ser87 and Thr56 in the loop of Bcl-2, which are known to be phosphorylated by p38α MAPK, impaired the ability Bcl-2 to interact with Nur77. Together, our results reveal a profound role of p38α MAPK in regulating the Nur77-Bcl-2 apoptotic pathway through its modulation of Nur77 expression, Bcl-2 phosphorylation, and their interaction.
Highlights
Nur77, an early immediate-response gene, is perhaps the most potent pro-apoptotic member of the nuclear receptor superfamily [1,2,3,4]
HeLa229 cells treated with vehicle or with CCE9 at 5, 10, 20 μM for 3 hr were examined for levels of Nur77 transcript by reverse transcriptionPCR (RT-PCR)
In studying the apoptotic effect of CCE9, we provided evidence here that it could induce apoptosis of various cancer cells through its activation of the Nur77Bcl-2 apoptotic pathway
Summary
Nur ( called TR3, NGFI-B, or NR4A1), an early immediate-response gene, is perhaps the most potent pro-apoptotic member of the nuclear receptor superfamily [1,2,3,4]. Besides being a nuclear transcriptional factor, Nur acts nongenomically in the cytoplasm by targeting mitochondria to induce apoptosis in response to certain apoptotic stimuli [5,6,7,8,9,10,11,12,13,14,15]. Mitochondrial targeting of Nur involves its interaction with Bcl-2 [7, 13, 15,16,17,18]. How the binding of Nur to the loop of Bcl-2 is regulated remains undefined
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