A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function
A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function
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DOI：
10.1038/sj.onc.1204139
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发表时间：
2001-02-08
期刊：
影响因子：
8
通讯作者：
Hay, N
中科院分区：
文献类型：
--
作者：
Kokontis, JM;Wagner, AJ;Hay, N
肿瘤抑制因子p53是细胞周期阻滞和程序性细胞死亡（凋亡）的诱导因子，p53诱导细胞周期阻滞的能力与其诱导基因转录的能力有关，如细胞周期蛋白依赖性激酶抑制因子p21。然而，p53介导的凋亡对转录激活的依赖性仍然是控制性的。温度敏感性（TS）p53等位基因的异位表达诱导p53靶基因的表达，并引起G1和G2/M细胞周期阻滞后，转移到允许的温度。异位表达相同的ts p53等位基因与两个额外的点突变（Gln 22，Ser 23），废除p53转录激活没有诱导p53靶基因和G1也G2/M细胞周期停滞。在HCT 116结肠癌细胞中，野生型p53的异位表达不引起凋亡，而反式激活缺陷的p53突变体诱导凋亡。野生型p53诱导凋亡的能力在p21缺失的HCT 116细胞中恢复，然而，在p21缺失细胞中，p53的反式激活缺陷突变体仍然是比野生型p53更有效的细胞凋亡介体。虽然Gln 22、Ser 23反式激活p53靶基因的能力减弱，但仍保留了抑制Bcl-2表达的能力。因此，我们的结论是，虽然异位表达的野生型p53可以诱导G1和G2/M;I逮捕，在p21依赖的方式，没有细胞凋亡，p53突变缺陷的反式激活eluvial细胞凋亡，而不诱导细胞周期阻滞。此外，p53的抗凋亡功能依赖于反式激活，并与细胞周期停滞有关。结果强烈地表明，反式激活缺陷突变体是更有效的凋亡诱导剂，因为它失去了其抗凋亡功能，并保留了其抑制促凋亡基因如Bcl-2的能力。这些结果意味着在基因治疗方法中使用反式激活缺陷型p53或使用将突变型p53转化为反式激活缺陷型p53的药物，凋亡的独立介导物可能是比目前使用野生型p53的方法有效得多的治疗方法。
The tumor suppressor p53 is an inducer of cell cycle arrest and programmed cell death (apoptosis), The ability of p53 to induce cell cycle arrest is linked to its ability to induce transcription of genes such as the cyclin-dependent kinase inhibitor p21, However, the dependence of p53-mediated apoptosis on transcriptional activation remains control versial. Ectopic expression of a temperature-sensitive (ts) p53 allele induced expression of p53 target genes and elicited both G1 and G2/M cell cycle arrest upon shift to the permissive temperature. Ectopic expression of the same ts p53 allele with two additional point mutations (Gln22, Ser23) that abolish p53-transcriptional activation did not induce p53 target genes and G1 nor G2/M cell cycle arrest. In HCT116 colon carcinoma cells ectopic expression of wild type p53 does not elicit apoptosis whereas p53 mutant deficient in trans-activation induces apoptosis, The ability of wild type p53 to induce apoptosis is restored in HCT116 cells that are null for p21, However, the trans-activation deficient mutant of p53 is still more potent mediator of apoptosis than wild type p53 in the p21 null cells. Although the ability of Gln22,Ser23 to trans-activate p53 target genes is diminished, it retains the ability to repress Bcl-2 expression. Thus, we conclude that while ectopic expression of wild type p53 can induce both G1 and G2/M;I arrest, in a p21 dependent manner, without apoptosis, a p53 mutant defective in transactivation elicits apoptosis without inducing cell cycle arrest. Further, the anti-apoptotic function of p53 is dependent on trans-activation and is linked to cell cycle arrest. The results strongly suggest that the transactivation deficient mutant is a more potent inducer of apoptosis because it lost its anti-apoptotic function and retains its ability to repress pro-apoptotic genes such as Bcl-2, Taken together, the results imply that employing a trans-activation deficient p53 in gene therapy approaches or the use of drugs that convert mutant p53 to a transactivation-independent mediator of apoptosis may be much more efficient therapeutic approaches than current approaches that employ wild type p53.