p53 Tumor Suppressor Pathway

真核生物基因组不断面临外源和内源诱变剂损害的威胁。因此，哺乳动物细胞已经进化出复杂的防御网络来维持基因组的稳定性。 p53 处于这些防御途径的十字路口。我们研究罕见的基因组不稳定和/或过早衰老疾病，例如 Bloom、Werner、Rothmund-Thomson 和 Li-Fraumeni 综合征，以深入了解普通人群中的 p53 功能。例如，p53 介导的细胞凋亡也受到人类 RecQ DNA 解旋酶家族的调节。 p53 还促进 DNA 修复途径。我们还发现了 p53 的转录辅助因子，即 ING2-5，它可以增强 p53 在细胞周期检查点、细胞凋亡和衰老中的效应功能。 ING4 通过与新型结合伴侣 liprin alpha1 相互作用来抑制细胞扩散和细胞迁移。 ING4 的新剪接变体也已被发现。我们正在继续研究由 ING 家族蛋白或控制端粒磨损的 POT1 和 p53 亚型调节的 p53 介导的复制衰老。

The eukaryote genome constantly faces the threat of damage from exogenous and endogenous mutagens. Mammalian cells, therefore, have evolved an intricate network of defenses to maintain genomic stability. p53 is at the crossroads of these defense pathways. We investigate rare genomic instability and/or premature aging diseases, e.g., Bloom, Werner, Rothmund-Thomson, and Li-Fraumeni Syndromes, to gain insight into p53 function in the general population. For example, p53-mediated apoptosis is also modulated by the human RecQ family of DNA helicases. p53 also facillitates DNA repair pathways. We have also discovered transcriptional cofactors of p53, i.e., ING2-5, that enhance p53 effector functions in cell cycle checkpoints, apoptosis, and senescence. ING4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. Novel splice variants of ING4 have also been discovered. We are continuing to study p53-mediated replicative senescence modulated by either ING family proteins or by POT1 and p53 isoforms that govern telomere attrition.