Cheng Yan, Qiu Feng, Tashiro Shin-ichi, Onodera Satoshi, Ikejima Takashi
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
Biochem Biophys Res Commun. 2008 Nov 21;376(3):483-8. doi: 10.1016/j.bbrc.2008.09.018. Epub 2008 Sep 15.
The object of this study was to investigate the molecular mechanisms mediating TNFalpha-induced apoptosis and autophagy in L929 cells. Herein, we found that the treatment of L929 cells with TNFalpha caused a time-dependent increase in p53 activity. The inhibition of p53 activation reduced TNFalpha-induced apoptosis and autophagy that were accompanied by the decrease in the levels of AIF, Beclin1 and LC3. Subsequently, TNFalpha activated ERK, JNK and p38 in apoptosis and autophagy, in which ERK/JNK played a promoting role whereas p38 played an inhibiting one. In addition, TNFalpha-induced p53 activation was reduced by ERK or JNK inhibition, but it was not affected by p38 inhibition. Further data showed that the inhibition of autophagy reduced TNFalpha-induced apoptosis in L929 cells. In conclusion, these results demonstrate that TNFalpha-induced MAPKs mediate p53 activation in apoptotic and autophagic cell death, as well as autophagy may amplify apoptosis when associated with a death signaling pathway.
本研究的目的是探究介导肿瘤坏死因子α（TNFα）诱导L929细胞凋亡和自噬的分子机制。在此，我们发现用TNFα处理L929细胞会导致p53活性随时间增加。抑制p53激活可减少TNFα诱导的凋亡和自噬，同时伴随凋亡诱导因子（AIF）、Beclin1和微管相关蛋白轻链3（LC3）水平降低。随后，TNFα在凋亡和自噬过程中激活细胞外调节蛋白激酶（ERK）、c-Jun氨基末端激酶（JNK）和p38，其中ERK/JNK起促进作用，而p38起抑制作用。此外，抑制ERK或JNK可降低TNFα诱导的p53激活，但不受p38抑制的影响。进一步的数据表明，抑制自噬可减少TNFα诱导的L929细胞凋亡。总之，这些结果表明，TNFα诱导的丝裂原活化蛋白激酶（MAPKs）在凋亡和自噬性细胞死亡中介导p53激活，并且当自噬与死亡信号通路相关时，自噬可能会放大凋亡。
