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MCL-1 依赖性白血病细胞比 BCL-2 依赖性白血病细胞对化疗更敏感。

MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts.

机构信息

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02052, USA.

出版信息

J Cell Biol. 2009 Nov 2;187(3):429-42. doi: 10.1083/jcb.200904049. Epub 2009 Oct 26.

DOI:10.1083/jcb.200904049
PMID:19948485
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2779245/
Abstract

Myeloid cell leukemia sequence 1 (MCL-1) and B cell leukemia/lymphoma 2 (BCL-2) are anti-apoptotic proteins in the BCL-2 protein family often expressed in cancer. To compare the function of MCL-1 and BCL-2 in maintaining cancer survival, we constructed complementary mouse leukemia models based on Emu-Myc expression in which either BCL-2 or MCL-1 are required for leukemia maintenance. We show that the principal anti-apoptotic mechanism of both BCL-2 and MCL-1 in these leukemias is to sequester pro-death BH3-only proteins rather than BAX and BAK. We find that the MCL-1-dependent leukemias are more sensitive to a wide range of chemotherapeutic agents acting by disparate mechanisms. In common across these varied treatments is that MCL-1 protein levels rapidly decrease in a proteosome-dependent fashion, whereas those of BCL-2 are stable. We demonstrate for the first time that two anti-apoptotic proteins can enable tumorigenesis equally well, but nonetheless differ in their influence on chemosensitivity.

摘要

髓系细胞白血病序列 1（MCL-1）和 B 细胞白血病/淋巴瘤 2（BCL-2）是 BCL-2 蛋白家族中的抗凋亡蛋白，通常在癌症中表达。为了比较 MCL-1 和 BCL-2 在维持癌症生存中的功能，我们构建了基于 Emu-Myc 表达的互补小鼠白血病模型，其中白血病的维持需要 BCL-2 或 MCL-1。我们表明，在这些白血病中，BCL-2 和 MCL-1 的主要抗凋亡机制是隔离促凋亡 BH3 仅蛋白，而不是 BAX 和 BAK。我们发现，依赖 MCL-1 的白血病对通过不同机制作用的广泛化疗药物更敏感。在这些不同治疗方法中共同的是，MCL-1 蛋白水平以依赖蛋白酶体的方式迅速下降，而 BCL-2 的水平则稳定。我们首次证明，两种抗凋亡蛋白可以同样有效地促进肿瘤发生，但在对化疗药物的敏感性方面仍然存在差异。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/0cddcb60039b/JCB_200904049_GS_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/44276af337e6/JCB_200904049_GS_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/e7101ab72fd5/JCB_200904049_RGB_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/707655a7b202/JCB_200904049_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/2dc4863ed6f8/JCB_200904049_GS_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/e795bc93808a/JCB_200904049_GS_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/1dd6c87398eb/JCB_200904049_GS_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/059c53f39549/JCB_200904049_RGB_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/b5e51e01f893/JCB_200904049_GS_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/942321401822/JCB_200904049_GS_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/0cddcb60039b/JCB_200904049_GS_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/44276af337e6/JCB_200904049_GS_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/e7101ab72fd5/JCB_200904049_RGB_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/707655a7b202/JCB_200904049_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/2dc4863ed6f8/JCB_200904049_GS_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/e795bc93808a/JCB_200904049_GS_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/1dd6c87398eb/JCB_200904049_GS_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/059c53f39549/JCB_200904049_RGB_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/b5e51e01f893/JCB_200904049_GS_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/942321401822/JCB_200904049_GS_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05d3/2779245/0cddcb60039b/JCB_200904049_GS_Fig10.jpg

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