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，BLM解旋酶促进人类细胞中的Mus81内切酶活性，而p53控制这种相互作用。p53介导的细胞凋亡也受人类DNA解旋酶家族的调控。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。我们正在继续研究由ING家族蛋白或控制端粒磨损的POT1和WRN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, BLM helicase facilitates Mus81 endonuclease activity in human cells and p53 governs this interaction. 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. We are continuing to study p53-mediated replicative senescence modulated by either ING family proteins or by POT1 and WRN that govern telomere attrition.