Huang S M, Schönthal A H, Stallcup M R
Department of Pathology, University of Southern California, Los Angeles, California, CA 90089, USA.
Oncogene. 2001 Apr 19;20(17):2134-43. doi: 10.1038/sj.onc.1204298.
A recently discovered potential tumor suppressor protein, Zac1, was previously shown to promote cell cycle arrest and apoptosis, and to act as a positive or negative transcriptional cofactor for nuclear receptors. Since these activities are common to Zac1 and p53, we tested for a functional interaction between these two proteins by investigating possible effects of Zac1 on the transcriptional activator function of p53. Zac1 specifically enhanced the activity of p53-responsive promoters in cells expressing wild type p53. The same promoters were not activated by Zac1 in cells lacking functional p53, but the Zac1 effect was restored by co-expression of p53. Zac1 bound to p53 and enhanced the activity of p53 or its N-terminal transcriptional activation domain fused to the DNA binding domain of Gal4. These results indicate that Zac1 served as a transcriptional coactivator for p53. The enhancement of p53 activity by Zac1 was much more dramatic in HeLa cells than in other cell lines tested. HeLa cells express human papillomavirus type 18 E6 protein which inactivates and causes the degradation of p53. Physical and functional interactions observed between Zac1 and E6 protein indicated that the dramatic activity of Zac1 in HeLa cells was due not only to Zac1's coactivator effect on p53, but also to the ability of Zac1 to reverse E6 inhibition of p53.
最近发现的一种潜在肿瘤抑制蛋白Zac1，此前已被证明可促进细胞周期停滞和凋亡，并作为核受体的正性或负性转录辅因子发挥作用。由于这些活性是Zac1和p53共有的，我们通过研究Zac1对p53转录激活功能的可能影响，来测试这两种蛋白之间的功能相互作用。Zac1特异性增强了表达野生型p53的细胞中p53反应性启动子的活性。在缺乏功能性p53的细胞中，相同的启动子不会被Zac1激活，但通过共表达p53可恢复Zac1的作用。Zac1与p53结合，并增强了p53或其与Gal4 DNA结合结构域融合的N端转录激活结构域的活性。这些结果表明Zac1作为p53的转录共激活因子发挥作用。与其他测试的细胞系相比，Zac1对HeLa细胞中p53活性的增强作用更为显著。HeLa细胞表达人乳头瘤病毒18型E6蛋白，该蛋白可使p53失活并导致其降解。在Zac1与E6蛋白之间观察到的物理和功能相互作用表明，Zac1在HeLa细胞中的显著活性不仅归因于Zac1对p53的共激活作用，还归因于Zac1逆转E6对p53抑制的能力。
