Wang Yubao, Manokaran Cherubin, Huang Kevin, Schaffhausen Brian, Roberts Thomas M
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2426862122. doi: 10.1073/pnas.2426862122. Epub 2025 Jul 3.
The study of DNA tumor viruses has revolutionized cancer biology, partly by virtue of the unique capabilities of viral oncoproteins to manipulate key proteins and pathways involved in tumorigenesis. We find a high affinity and selective binding of the polyoma small T antigen (PyST) with the transcription cofactor TAZ. By engineering a degradable version of PyST, we demonstrate that, when TAZ activity is modulated by PyST, a surprisingly small number of genes have altered expression and thus are candidate transcription targets of TAZ. Notably, knocking out TAZ, or its target genes CTGF or CYR61, abolishes the growth-promoting properties of PyST that are evident upon growth factor withdrawal. Therefore, by controlling the protein abundance of PyST and consequently TAZ activity, we find that TAZ is a transcriptional coactivator that can achieve important biological effects by acting on a limited number of gene targets.
对DNA肿瘤病毒的研究彻底改变了癌症生物学，部分原因在于病毒癌蛋白具有独特能力，能够操纵参与肿瘤发生的关键蛋白和信号通路。我们发现多瘤病毒小T抗原（PyST）与转录辅因子TAZ具有高亲和力和选择性结合。通过构建可降解版本的PyST，我们证明，当TAZ活性受PyST调节时，只有极少数基因的表达发生改变，因此这些基因是TAZ潜在的转录靶点。值得注意的是，敲除TAZ或其靶基因CTGF或CYR61，会消除PyST在生长因子撤除后所表现出的促生长特性。因此，通过控制PyST的蛋白丰度进而调控TAZ活性，我们发现TAZ是一种转录共激活因子，通过作用于有限数量的基因靶点即可实现重要的生物学效应。
