Bcl-XL is qualitatively different from and ten times more effective than Bcl-2 when expressed in a breast cancer cell line.
Bcl-XL is qualitatively different from and ten times more effective than Bcl-2 when expressed in a breast cancer cell line.
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DOI：
10.1186/1471-2407-6-213
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发表时间：
2006-08-23
期刊：
影响因子：
3.8
通讯作者：
Andrews DW
中科院分区：
文献类型：
--
作者：
Fiebig AA;Zhu W;Hollerbach C;Leber B;Andrews DW
Bcl-2和Bcl-XL是抑制由多种刺激引起的细胞凋亡的抗细胞凋亡旁系同源物，并且在癌症发展和对治疗的抗性中起关键作用。许多临床研究表明，这些抗凋亡蛋白在肿瘤中的表达与不良预后有关。因此，已经假设在细胞中Bcl-2和Bcl-XL之间的本质差异涉及表达的调节，并且它们在其他方面功能相似。为了研究这个问题，我们比较了蛋白质和Bcl-2和Bcl-XL的突变体的功能，特别是针对不同的亚细胞位点。我们产生了稳定表达已知量Bcl-2或Bcl-XL的人乳腺癌细胞系MCF-7的克隆，如通过定量免疫印迹所确定的。在MCF-7和Rat-1成纤维细胞中研究了表达等量野生型和Bcl-2和Bcl-XL突变体的克隆，其亚细胞定位限于细胞质、内质网或线粒体外膜。在MCF-7细胞中，我们测量了这些蛋白质在防止由四种不同试剂（阿霉素、神经酰胺、毒胡萝卜素、TNF-α）诱导的凋亡中的功能活性。用足叶乙甙和低血清比较Bcl-2、Bcl-XL和内质网突变体对成纤维细胞凋亡的诱导作用。我们注意到细胞中这两种抗凋亡蛋白的功能活性的定性和定量差异：位于内质网的Bcl-2抑制神经酰胺和毒胡萝卜素诱导的凋亡，但不抑制阿霉素或TNFα诱导的凋亡，而内质网的Bcl-XL对所有四种药物都有活性。在成纤维细胞中，定位于ER的Bcl-2并不能阻止依托泊苷引起的细胞死亡，而同一位置的Bcl-XL却能阻止依托泊苷引起的细胞死亡。最后，在MCF-7细胞中，Bcl-XL在抑制多柔比星诱导的细胞凋亡方面的活性比Bcl-2高约10倍。这种差异可以表现为克隆存活率的巨大差异。当在相同的细胞背景下进行检查时，Bcl-2和Bcl-XL抑制细胞凋亡的效力存在很大差异，部分是由特定亚细胞途径抑制的差异介导的。
Bcl-2 and Bcl-XL are anti-apoptotic paralogues that inhibit apoptosis elicited by a wide variety of stimuli, and play critical roles in cancer development and resistance to treatment. Many clinical studies have indicated that expression of these anti-apoptotic proteins in tumours is associated with poor prognosis. It has therefore been assumed that in cells the essential difference between Bcl-2 and Bcl-XL involves regulation of expression and that they are otherwise functionally similar. To examine this issue, we have compared the function of the proteins and of mutants of Bcl-2 and Bcl-XL specifically targeted to different subcellular sites. We generated clones of the human breast cancer line MCF-7 stably expressing known amounts of Bcl-2, or Bcl-XL as determined by quantitative immunoblotting. Clones expressing equivalent amounts of wild-type and mutants of Bcl-2 and Bcl-XL with subcellular localization restricted to the cytoplasm, endoplasmic reticulum or outer mitochondrial membrane were studied in both MCF-7 and Rat-1 fibroblasts. In MCF-7 cells we measured the functional activities of these proteins in preventing apoptosis induced by four different agents (doxorubicin, ceramide, thapsigargin, TNF-α). Etoposide and low serum were used to compare the effect of Bcl-2, Bcl-XL and mutants located at the endoplasmic reticulum on induction of apoptosis in fibroblasts. We noted both qualitative and quantitative differences in the functional activity of these two anti-apoptotic proteins in cells: Bcl-2 localized to the endoplasmic reticulum inhibits apoptosis induced by ceramide and thapsigargin but not by doxorubicin or TNFα, while Bcl-XL at the endoplasmic reticulum is active against all four drugs. In fibroblasts Bcl-2 localized to the ER did not prevent cell death due to etoposide whereas Bcl-XL in the same location did. Finally in MCF-7 cells, Bcl-XL is approximately ten times more active than Bcl-2 in repressing apoptosis induced by doxorubicin. This difference can be manifest as a large difference in clonal survival. When examined in the same cellular context, Bcl-2 and Bcl-XL differ substantially in the potency with which they inhibit apoptosis, mediated in part by differences in the inhibition of specific subcellular pathways.
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影响因子：
8
作者：
Annis, MG;Zamzami, N;Andrews, DW
通讯作者：
Andrews, DW
影响因子：
11.4
作者：
Dlugosz, Paulina J.;Billen, Lieven P.;Andrews, David W.
通讯作者：
Andrews, David W.
DOI：
10.1073/pnas.94.8.3668
发表时间：
1997-04-15
影响因子：
11.1
作者：
Hsu, YT;Wolter, KG;Youle, RJ
通讯作者：
Youle, RJ
影响因子：
78.5
作者：
Brown, JM;Attardi, LD
通讯作者：
Attardi, LD
影响因子：
11.4
作者：
Fadeel, B;Hassan, Z;Zhivotovsky, B
通讯作者：
Zhivotovsky, B