Apoptosis triggered by Myc-induced suppression of Bcl-XL or Bcl-2 is bypassed during lymphomagenesis
Apoptosis triggered by Myc-induced suppression of Bcl-XL or Bcl-2 is bypassed during lymphomagenesis
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DOI：
10.1128/mcb.21.15.5063-5070.2001
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发表时间：
2001-08-01
影响因子：
5.3
通讯作者：
Cleveland, JL
中科院分区：
文献类型：
--
作者：
Eischen, CM;Woo, D;Cleveland, JL
增强的Bcl2表达抑制Myc诱导的细胞凋亡，并与Myc协同转化。在此，我们报道了Bcl2和Myc在转化造血细胞中的协同作用实际上反映了Myc诱导的一条通路，选择性地抑制BclX-L或Bcl2抗凋亡蛋白的表达。Myc激活抑制原代髓系和淋巴系祖细胞培养的BclX-L基因和蛋白水平，Myc抑制癌前B细胞中BclX-L和Bcl2的表达。Myc抑制bcl-X RNA水平需要从头合成蛋白质，这表明抑制是间接的。重要的是，在Myc诱导的肿瘤发生过程中，Myc对Bcl2或BclX-L的抑制作用被破坏，因为在E Mu-myc转基因小鼠发生的所有淋巴瘤中，超过一半的Bcl2和/或BclX-L水平显著升高。Bc l-2和/或bc l-X-L的过表达与肿瘤细胞ARF或P53功能的丧失无关，表明这两条凋亡通路是独立失活的。因此，抑制Bc l-X-L或Bc l-2的表达代表了Myc诱导的生理性细胞凋亡途径，在淋巴肿瘤的发生过程中经常被绕过。
Enforced Bcl-2 expression inhibits Myc-induced apoptosis and cooperates,vith Myc in transformation. Here we report that the synergy between Bcl-2 and Myc in transforming hematopoietic cells in fact reflects a Myc-induced pathway that selectively suppresses the expression of the Bcl-X-L or Bcl-2 antiapoptotic protein. Myc activation suppresses Bcl-X-L RNA and protein levels in cultures of primary myeloid and lymphoid progenitors, and Bcl-X-L and Bcl-2 expression is inhibited by Myc in precancerous B cells from E mu -myc transgenic mice. The suppression of bcl-X RNA levels by Myc requires de novo protein synthesis, indicating that repression is indirect. Importantly, the suppression of Bcl-2 or Bcl-X-L by Myc is corrupted during Myc-induced tumorigenesis, as Bcl-2 and/or Bcl-X-L levels are markedly elevated in over one-half of all lymphomas arising in E mu -myc transgenic mice. Bcl-2 and/or Bcl-X-L overexpression did not correlate with loss of ARF or p53 function in tumor cells, indicating that these two apoptotic pathways are inactivated independently. Therefore, the suppression of Bcl-X-L or Bcl-2 expression represents a physiological Myc-induced apoptotic pathway that is frequently bypassed during lymphomagenesis.