Activation of the Rb/E2F1 pathway by the nonproliferative p38 MAPK during fAs (APO1/CD95)-mediated neuronal apoptosis

被引:60
作者
Hou, ST
Xie, XQ
Baggley, A
Park, DS
Chen, G
Walker, T
机构
[1] Natl Res Council Canada, Inst Biol Sci, Expt Stroke Grp, Ottawa, ON K1A 0R6, Canada
[2] Univ Ottawa, Neurosci Res Inst, Ottawa, ON K1H 8M5, Canada
关键词
D O I
10.1074/jbc.M206336200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Aberrant activation of the Rb/E2F1 pathway in cycling cells, in response to mitogenic or nonmitogenic stress signals, leads to apoptosis through hyperphosphorylation of Rb. To test whether in postmitotic neurons the Rb/E2F1 pathway can be activated by the nonmitogenic stress signaling, we examined the role of the p38 stress-activated protein kinase (SAPK) in regulating Rb phosphorylation in response to Fas (CD95/APO1)-mediated apoptosis of cultured cerebellar granule neurons (CGNs). Anti-Fas antibody induced a dramatic and early activation of p38. Activated p38 was correlated with the induction of hyperphosphorylation of both endogenous and exogenous Rb. The p38-selective inhibitor, SB203580, attenuated such an increase in pRb phosphorylation and significantly protected CGNs from Fas-induced apoptosis. The cyclin-dependent kinase-mediated Rb phosphorylation played a lesser role in this neuronal death paradigm, since cyclin-dependent kinase inhibitors, such as olomoucine, roscovitine, and flavopiridol, did not significantly prevent anti-Fas antibody-evoked neuronal apoptosis. Hyperphosphorylation of Rb by p38 SAPK resulted in the release of Rb-bound E2F1. Increased E2F1 modulated neuronal apoptosis, since E2Fl-/- CGNs were significantly less susceptible to Fas-mediated apoptosis in comparison with the wildtype CGNs. Taken together, these studies demonstrate that neuronal Rb/E2F1 is modulated by the nonproliferative p38 SAPK in Fas-mediated neuronal apoptosis.
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页码:48764 / 48770
页数:7
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