The E3 ligase APC/C-Cdh1 regulates MEF2A-dependent transcription by targeting SUMO-specific protease 2 for ubiquitination and degradation.

Activity-dependent stimuli induced a calcineurin-mediated dephosphorylation of the transcriptional factor MEF2A at serine408 and promoted a switch from SUMOylation to acetylation at lysine403 which led to MEF2A transcriptional activation. We previously identified SENP2 is the de-SUMOylation enzyme for MEF2A and promotes MEF2A-dependent transcription. We report here a requirement for APC(Cdh1)-SENP2-MEF2A axis in the regulation of MEF2A transcriptional activation. APC(Cdh1) interacts with and targets SENP2 for ubiquitination and destruction in the cytoplasm by recognizing a conserved canonical D-box motif in SENP2. Moreover, Cdh1 regulates the transcriptional activity of MEF2A in a SENP2 dependent manner. Activity-dependent stimuli prevented APC(Cdh1)-induced SENP2 ubiquitination, promoted SENP2 nuclear accumulations, and caused MEF2A de-SUMOylation and MEF2A acetylation, leading to MEF2A transcriptional activation. Thus, our findings defined a post-transcriptional mechanism underlying activity-dependent stimuli-induced MEF2A transcriptional activation.

[The effects of general anesthesia combined with epidural anesthesia on the stress response in thoracic surgery].

OBJECTIVE: To study the effects of general anesthesia combined with epidural anesthesia (GEA) and pure general anesthesia (GA) on the surgical stress response and cytokines in pulmonary surgery. METHODS: Twenty patients submitted to elective pulmonary surgery were randomly divided into 2 groups of 10 patients: GEA group receiving general anesthesia combined with thoracic epidural analgesia and GA group receiving only general anesthesia. Blood samples were taken before induction, at incision, 2 h, 4 h, 6 h following the incision, and in the 1st and 3rd postoperative day. IL-6, ACTH and cortisol were detected with radioimmunoassay. RESULTS: (1). The concentration of ACTH was similar in the 2 groups before operation, was remarkably increased 2 hours postoperatively (P < 0.05), reached the peak values 2 approximately 4 hours after the incision in most patients (P < 0.01), and returned to the preoperative levels one day after operation without a significant difference at every time point between the two groups. (2). The concentration of cortisol decreased transiently during incision in the GEA group (P < 0.05), then increased gradually, was significantly higher than the preoperative level (P < 0.01), and remained at the high level till the morning of the 1st day after operation (P < 0.01). In the GA group the cortisol concentration was higher than that before operation 2 hours after incision (P < 0.01), and remained at the level higher than that before operation 4 h and 6 h after incision (P < 0.01), and returned to the normal level by the morning of the 3rd day. The cortisol concentration 2 hours after incision in GEA group was significantly lower than that in GA group (P < 0.05), however, the peak concentrations of these 2 groups were not significantly different (P > 0.05). In the GA group the IL-6 concentration began to increase after operation, became significantly different from that before operation 4 hours after operation (P < 0.01), reached the peak level in the morning of the first postoperative day (P < 0.05), and returned to the preoperative level in the third day. In the GEA group the IL-6 concentration began to increase 2 hours after operation (P < 0.05), and returned to the preoperative level in the morning of the first postoperative day. The concentration of IL-6 was positively correlated with that of cortisol (r = 0.231). CONCLUSION: Pulmonary surgery performed with two different anesthetic techniques causes inflammatory cytokine responses. The additional epidural anesthesia doesn't influence cytokine production. It incompletely inhibits the stress response in the early phase. IL-6 and cortisol may have some effects on each other.