c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells
c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells
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DOI：
10.1038/sj.onc.1203541
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发表时间：
2000-04-27
期刊：
影响因子：
8
通讯作者：
León, J
中科院分区：
文献类型：
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作者：
Ceballos, E;Delgado, MD;León, J
C-myc原癌基因正向调节细胞增殖，在许多实体瘤和白血病中发现c-myc过表达，本研究以K562人髓系白血病细胞株为模型，研究c-myc与P53的功能相互作用。使用两种不同的方法，我们建立了条件表达c-Myc或p53的K562细胞系。细胞表达突变体P53(Vall35)，该突变体在32℃时呈温和型构象，而c-Myc通过锌诱导表达载体诱导。我们发现轻度构象的P53诱导K562细胞生长停滞和凋亡。C-Myc的表达可显著抑制D53在p21(WAF1)、FAX和巨细胞病毒启动子上的转录活性。C-Myc对p21(WAF1)反式激活的损伤可通过c-Myc-雌激素受体融合蛋白的转染和锌对c-myc的诱导而得到证实。P53介导的p21(WAF1)mRNA蛋白上调仅被Myc显著抑制，而Bas水平不受影响。在野生型表达P53的K562细胞中，c-Myc持续增强细胞周期蛋白依赖性激酶2的活性。这些结果表明，c-Myc的过表达可能拮抗P53的促凋亡功能，从而为常见的c-myc在人类癌症中的失控提供了分子机制。
c-myc protooncogene positively regulates cell proliferation and overexpression of c-myc is found in many solid tumors and leukemias, In the present study we used the K562 human myeloid leukemia cell line as a model to study the functional interaction between c-Myc and p53. Using two different methods, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53(Vall35) mutant, which adopts a mild-type conformation at 32 degrees C, while c-Myc induction was achieved with a zinc-inducible expression vector. We found that p53 in mild-type conformation induces growth arrest and apoptosis of K562. Expression of c-Myc significantly attenuated apoptosis and impaired the transcriptional activity of D53 on p21(WAF1), fax and cytomegalovirus promoters. The impairment of p21(WAF1) transactivation by c-Myc was confirmed by transfection of a c-Myc-estrogen receptor fusion protein and by induction of c-myc by zinc in transfected cells. Also, p53-mediated up-regulation of p21(WAF1) mRNA protein mere significantly reduced by Myc, while Bas levels were unaffected. Consistently, c- Myc increased cyclin-dependent kinase 2 activity in K562 cells expressing p53 in wild-type conformation These results suggest that c-Myc overexpression may antagonize the pro-apoptotic function of p53, thus providing a molecular mechanism for frequently observed deregulation of c-myc in human cancer.