Serber Zach, Lai Helen C, Yang Annie, Ou Horng D, Sigal Martina S, Kelly Alexander E, Darimont Beatrice D, Duijf Pascal H G, Van Bokhoven Hans, McKeon Frank, Dötsch Volker
Graduate Group in Biophysics, University of California San Francisco, San Francisco, California 94143, USA.
Mol Cell Biol. 2002 Dec;22(24):8601-11. doi: 10.1128/MCB.22.24.8601-8611.2002.
The human genome is far smaller than originally estimated, and one explanation is that alternative splicing creates greater proteomic complexity than a simple count of open reading frames would suggest. The p53 homologue p63, for example, is a tetrameric transcription factor implicated in epithelial development and expressed as at least six isoforms with widely differing transactivation potential. In particular, p63alpha isoforms contain a 27-kDa C-terminal region that drastically reduces their activity and is of clear biological importance, since patients with deletions in this C terminus have phenotypes very similar to patients with mutations in the DNA-binding domain. We have identified a novel domain within this C terminus that is necessary and sufficient for transcriptional inhibition and which acts by binding to a region in the N-terminal transactivation domain of p63 homologous to the MDM2 binding site in p53. Based on this mechanism, we provide a model that explains the transactivation potential of homo- and heterotetramers composed of different p63 isoforms and their effect on p53.
人类基因组比最初估计的要小得多，一种解释是可变剪接产生的蛋白质组复杂性比简单计算开放阅读框所显示的要高。例如，p53 同源物 p63 是一种四聚体转录因子，参与上皮发育，并以至少六种具有广泛不同转录激活潜力的异构体形式表达。特别是，p63α 异构体包含一个 27 kDa 的 C 末端区域，该区域会大幅降低其活性，并且具有明确的生物学重要性，因为该 C 末端缺失的患者的表型与 DNA 结合域发生突变的患者非常相似。我们在这个 C 末端内鉴定出一个新的结构域，它对于转录抑制是必需且充分的，并且通过与 p63 的 N 末端转录激活域中与 p53 的 MDM2 结合位点同源的区域结合来发挥作用。基于这一机制，我们提供了一个模型，该模型解释了由不同 p63 异构体组成的同型和异型四聚体的转录激活潜力及其对 p53 的影响。
