Molecular Cell Biology Laboratory, The Smurfit Institute of Genetics, Trinity College, Dublin, Ireland.
Autophagy. 2011 Aug;7(8):922-3. doi: 10.4161/auto.7.8.15821. Epub 2011 Aug 1.
Although several oncogenes enhance autophagic flux, the molecular mechanism and consequences of oncogene-induced autophagy remain to be clarified. We have recently shown that expression of oncogenic H-Ras (V12) promotes autophagy through upregulation of Beclin 1 and the BH3-only protein Noxa. H-Ras-expressing cells undergo autophagic cell death as a result of Noxa-mediated displacement of Mcl-1 and Bcl-xL from Beclin 1. Oncogenic H-Ras-induced death is attenuated through knockdown of BECLIN 1, ATG5, or ATG7, or through overexpression of Mcl-1, Bcl-2, Bcl-xL and their close relatives. These observations suggest that high-intensity oncogene activation may be selected against by promoting excessive autophagy, leading to cell death. Consequently, such oncogenes may select for cells with a reduced capacity for autophagy, either through loss of a BECLIN 1 allele or through upregulation of negative regulators of Beclin 1, such as Bcl-2 family members.
虽然有几个癌基因增强了自噬通量，但癌基因诱导的自噬的分子机制和后果仍有待阐明。我们最近表明，致癌 H-Ras（V12）的表达通过上调 Beclin 1 和 BH3 仅蛋白 Noxa 促进自噬。由于 Noxa 介导的 Mcl-1 和 Bcl-xL 从 Beclin 1 的置换，表达 H-Ras 的细胞发生自噬性细胞死亡。通过敲低 BECLIN 1、ATG5 或 ATG7，或通过过表达 Mcl-1、Bcl-2、Bcl-xL 及其近亲，可以减弱致癌 H-Ras 诱导的死亡。这些观察结果表明，高强度癌基因激活可能通过促进过度自噬而被选择，导致细胞死亡。因此，这种癌基因可能通过丧失 BECLIN 1 等位基因或通过上调 Beclin 1 的负调节剂，如 Bcl-2 家族成员，选择自噬能力降低的细胞。
