E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis
E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis
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DOI：
10.1128/mcb.17.3.1049
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发表时间：
1997-03-01
影响因子：
5.3
通讯作者：
Hiebert, SW
中科院分区：
文献类型：
--
作者：
Nip, J;Strom, DK;Hiebert, SW
视网膜母细胞瘤（pRb）肿瘤抑制途径的突变，包括其细胞周期蛋白-cdk调节激酶或cdk抑制剂，是大多数癌症的标志，并允许不受限制的E2F-1转录因子活性，从而导致不受调节的G(1)至s期细胞周期进程。中等水平的E2F-1过表达在白细胞介素3 （IL3）依赖性32D中是耐受的。然而，当这些细胞被剥夺IL-3时，它会诱导细胞凋亡。然而，当E2F活性通过其异二聚体伙伴DP-1的共表达而增强时，生存因子的影响就被消除了。为了确定E2F-1的表达是否选择性地使细胞对细胞毒性药物敏感，我们研究了化疗药物和放射治疗在癌症治疗中的作用。当使用拓扑异构酶II抑制剂依托泊苷处理髓细胞时，E2F-1在髓细胞中的过表达优先使细胞凋亡敏感。虽然单独使用E2F-1可诱导中等水平的p53，且药物治疗可显著增加p53，但依托泊苷对过表达E2F-1的细胞的有害作用与p53的积累无关。Bcl-2和E2F-1在32D中的共表达。3细胞保护它们免受依托泊苷介导的凋亡。然而，Bcl-2在暴露于5-氟尿嘧啶和阿霉素时也能阻止这些细胞的凋亡，这两种物质对对照细胞也具有细胞毒性。用不损伤DNA的第二种拓扑异构酶II抑制剂ICRF-193预处理表达e2f -1的细胞，保护细胞免受依托泊苷诱导的凋亡。然而，ICRF-193与dna损伤剂共同诱导细胞凋亡。因此，在pRb通路突变导致E2F-1活性不调节的细胞中，拓扑异构酶II抑制和DNA损伤可以选择性地诱导p53非依赖性细胞凋亡。
Mutations in the retinoblastoma (pRb) tumor suppressor pathway including its cyclin-cdk regulatory kinases, or cdk inhibitors, are a hallmark of most cancers and allow unrestrained E2F-1 transcription factor activity, which leads to unregulated G(1)-to-S-phase cell cycle progression. Moderate levels of E2F-1 overexpression are tolerated in interleukin 3 (IL3)-dependent 32D.3 myeloid progenitor cells, yet this induces apoptosis when these cells are deprived of IL-3. However, when E2F activity is augmented by coexpression of its heterodimeric partner, DP-1, the effects of survival factors are abrogated. To determine whether enforced E2F-1 expression selectively sensitizes cells to cytotoxic agents, we examined the effects of chemotherapeutic agents and radiation used in cancer therapy. E2F-1 overexpression in the myeloid cells preferentially sensitized cells to apoptosis when they were treated with the topoisomerase II inhibitor etoposide. Although E2F-1 alone induces moderate levels of p53 and treatment with drugs markedly increased p53, the deleterious effects of etoposide in E2F-1-overexpressing cells were independent of p53 accumulation. Coexpression of Bcl-2 and E2F-1 in 32D.3 cells protected them from etoposide-mediated apoptosis. However, Bcl-2 also prevented apoptosis of these cells upon exposure to 5-fluorouracil and doxorubicin, which were also cytotoxic for control cells. Pretreating E2F-1-expressing cells with ICRF-193, a second topoisomerase II inhibitor that does not damage DNA, protected the cells from etoposide-induced apoptosis. However, ICRF-193 cooperated with DNA-damaging agents to induce apoptosis. Therefore, topoisomerase II inhibition and DNA damage can cooperate to selectively induce p53-independent apoptosis in cells that have unregulated E2F-1 activity resulting from mutations in the pRb pathway.