p53 Tumor Suppressor Pathway

真核生物基因组不断面临外源性和内源性诱变剂损伤的威胁。因此，哺乳动物细胞进化出了一个复杂的防御网络来维持基因组的稳定性。P53位于这些防御途径的十字路口。我们研究了罕见的基因组不稳定和/或早衰疾病，如Bloom、Werner、rothmond - thomson和Li-Fraumeni综合征，以深入了解p53在普通人群中的功能。例如，p53介导的细胞凋亡也可由人类DNA解旋酶的RecQ家族调节。p53也促进DNA修复途径。我们还发现了p53的转录辅助因子，即ING2-5，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通过与一种新的结合伙伴脂素α 1相互作用来抑制细胞扩散和细胞迁移。新的ING4剪接变体也被发现。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同工型调节的p53介导的复制性衰老。

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.