Nesbit C E, Fan S, Zhang H, Prochownik E V
Section of Hematology/Oncology, the Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Blood. 1998 Aug 1;92(3):1003-10.
The c-myc oncoprotein accelerates programmed cell death (apoptosis) after growth factor deprivation or pharmacological insult in many cell lines. We have shown that max, the obligate c-myc heterodimeric partner protein, also promotes apoptosis after serum withdrawal in NIH3T3 fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. We now show that c-myc- and max-overexpressing 32D cells differ in the nature of their apoptotic responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin (Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max overexpression increases sensitivity only to Camptothecin. Drug treatment of c-myc-overexpressing cells in the absence of IL-3 did not alter the spectrum of drug sensitivity other than to additively accelerate cell death. In contrast, enhanced sensitivity to Adriamycin, Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was revealed in max-overexpressing cells concurrently deprived of IL-3. Differential rates of apoptosis were not strictly correlated with the ability of the drugs to promote G1 or G2/M arrest. Ectopic expression of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc-overexpressing cells. These results provide mechanistic underpinnings for the idea that c-myc and max modulate distinct apoptotic pathways.
在许多细胞系中，c-myc癌蛋白在生长因子剥夺或药物损伤后会加速程序性细胞死亡（凋亡）。我们已经表明，max作为c-myc的 obligate异二聚体伴侣蛋白，在NIH3T3成纤维细胞血清撤除后或白细胞介素-3（IL-3）依赖的32D小鼠髓样细胞细胞因子剥夺后也会促进凋亡。我们现在表明，过表达c-myc和max的32D细胞在撤除IL-3或用化疗化合物处理后的凋亡反应性质上有所不同。在有IL-3存在的情况下，c-myc过表达增强了32D细胞对依托泊苷（Sigma，圣路易斯，密苏里州）、阿霉素（Pharmacia，哥伦布，俄亥俄州）和喜树碱（Sigma）的敏感性，而max过表达仅增加对喜树碱的敏感性。在没有IL-3的情况下对过表达c-myc的细胞进行药物处理，除了相加性加速细胞死亡外，并未改变药物敏感性谱。相反，在同时剥夺IL-3的过表达max的细胞中，显示出对阿霉素、依托泊苷和紫杉醇（百时美施贵宝，普林斯顿，新泽西州）的敏感性增强。不同的凋亡速率与药物促进G1或G2/M期阻滞的能力并不严格相关。Bcl-2或Bcl-XL的异位表达在两种细胞系中均阻断了药物诱导的凋亡。相反，虽然Bcl-2在两种细胞系中对IL-3撤除均阻断凋亡，但Bcl-XL在过表达max的细胞中阻断凋亡，而在过表达c-myc的细胞中则不然。这些结果为c-myc和max调节不同凋亡途径这一观点提供了机制基础。
