Procaspase 8 and Bax Are Up-regulated by Distinct Pathways in Streptococcal Pyrogenic Exotoxin B-induced Apoptosis

Abstract

We have previously identified integrin ␣ v ␤ 3 and Fas as receptors for the streptococcal pyrogenic exotoxin B (SPE B), and G308S, a mutant of SPE B that binds to Fas only. In the current study we found that after binding to ␣ v ␤ 3 , SPE B stimulated the tyrosine phosphorylation of JAK2 and STAT1. STAT1 tyrosine phosphorylation was inhibited by a JAK2 inhibitor, AG490, short interfering RNA (siRNA) silencing of JAK2, and anti-␣ V ␤ 3 antibody. AG490 also decreased the binding of tyrosine-phosphorylated STAT1 to the procaspase 8 promoter, decreasing procaspase 8 expression, suggesting that SPE B up-regulates procaspase 8 expression via the JAK2/STAT1 pathway. Alternatively, both SPE B and G308S increased STAT1 phosphorylation at serine 727, which was inhibited by anti-Fas antibody, a p38 inhibitor, SB203580, and siRNA silencing of p38. In addition, SPE B and G308S increased binding of serine-phosphorylated STAT1 to the Bax promoter and Bax expression, which was decreased by SB203580. SPE B and G308S-stimulated Bax expression was also inhibited by anti-Fas antibody. These findings suggest that Fas mediate SPE B-induced Bax expression through p38. Silencing of JAK2 or p38 by siRNA blocked procaspase 8 expression, whereas only p38 siRNA decreased Bax expression. Furthermore, JAK2 inhibition and p38 inhibition reduced SPE B-induced apoptosis, but only p38 inhibition blocked G308S-induced apoptosis.

Glycogen synthase kinase-3 and p38 MAPK are required for opioid-induced microglia apoptosis

“…4C), its consequence on the p38 MAPK function was next examined in BV-2 and mouse primary microglial cells. We pretreated BV-2 and mouse primary microglial cells with the specific p38 MAPK inhibitor SB 203580 (Chang et al, 2009) and then treated the cells in the presence or absence of morphine. Apoptotic cells were examined by TUNEL assay.…”

“…Inhibition of p38 MAPK by p38 inhibitor SB203580 significantly attenuated tolerance to morphine analgesia (Cui et al, 2006). P38 MAPK seems to sensitize cells to apoptosis by up-regulating Bax (Porras et al, 2004; Chang et al, 2009), a pro-apoptotic member of Bcl-2 family (Porras et al, 2004; Chang et al, 2009). But the role of p38 in morphine-promoted microglia apoptosis is unknown.…”

Tubeimoside I sensitizes cisplatin in cisplatin-resistant human ovarian cancer cells (A2780/DDP) through down-regulation of ERK and up-regulation of p38 signaling pathways

“…Bcl2 is the first gene proven to be a negative regulator of cell death and to protect cells from undergoing apoptosis induced by exogenous stimuli, whereas Bax is a proapoptotic regulator that promotes or accelerates cell death (33). Our results provide evidence that the activation of the intrinsic apoptotic pathway via a Bcl-2 and Bax-dependent mechanism could be a possible mechanism by which TBMS1 enhances CDDP-induced apoptosis (Fig.…”

Phosphorylation of signal transducer and activator of transcription 1 reduces bortezomib-mediated apoptosis in cancer cells

“…8 Evidence also suggests that activated STAT1 may regulate apoptosis by enhancing the transcription of procaspase-8, Bax, Bcl-2, and Bcl-X. 10 STAT1 phosphorylated at serine 727 and tyrosine 701 can induce apoptotic cell death in heart, brain, and liver tissues following ischemia–reperfusion injury. In addition, it has been demonstrated that both serine 727 and tyrosine 701 of STAT1 are phosphorylated in response to JAK and p38 activation in Streptococcal pyrogenic exotoxin B-induced apoptosis.…”

“…In addition, it has been demonstrated that both serine 727 and tyrosine 701 of STAT1 are phosphorylated in response to JAK and p38 activation in Streptococcal pyrogenic exotoxin B-induced apoptosis. 10 Although the proapoptotic effects of STAT1 have been widely reported, only a few studies have focused on its potential antiapoptotic properties. 11, 12 …”