Waterman M J, Waterman J L, Halazonetis T D
Department of Molecular Oncology, Wistar Institute, Philadelphia, PA 19104-4268, USA.
Cancer Res. 1996 Jan 1;56(1):158-63.
The tetramerization domain of p53 is required for efficient tumor suppressor activity. This domain, however, also allows wild-type p53 to heterooligomerize with dominant negative tumor-derived p53 mutants. We explored the feasibility of substituting the native tetramerization domain of wild-type p53 with an engineered leucine zipper that assembles as a four-stranded coiled coil. The engineered zipper drove p53 tetramerization in vitro and p53 function in vivo. Furthermore, it alleviated transdominant inhibition by tumor-derived p53 mutants, implying that dominant negative mutants act by hetero-oligomerizing with wild-type p53. The ability of the engineered zipper to drive tetramerization was critical for p53 function, since p53 dimers, formed by substituting the p53 tetramerization domain with a native leucine zipper, were weak tumor suppressors.
p53的四聚化结构域是高效肿瘤抑制活性所必需的。然而，该结构域也允许野生型p53与显性负性肿瘤来源的p53突变体异源寡聚化。我们探索了用工程化亮氨酸拉链替代野生型p53天然四聚化结构域的可行性，该亮氨酸拉链组装成四链卷曲螺旋结构。工程化拉链在体外驱动p53四聚化，在体内驱动p53发挥功能。此外，它减轻了肿瘤来源的p53突变体的反式显性抑制作用，这意味着显性负性突变体通过与野生型p53异源寡聚化发挥作用。工程化拉链驱动四聚化的能力对p53功能至关重要，因为用天然亮氨酸拉链替代p53四聚化结构域形成的p53二聚体是弱肿瘤抑制因子。
