Cell Senescence, Carcinogenesis, and Aging

衰老是人类癌症的主要危险因素。我们的项目是利用细胞和动物模型阐明衰老和癌症的分子机制。我们已经表明，正常的人类细胞具有端粒酶依赖性和独立的细胞衰老途径，这两者都是肿瘤抑制机制。染色体3 p21（端粒酶hTERT基因的转录抑制子）和染色体1q42.3（其功能独立于端粒酶调节）上的衰老基因将通过位置和功能克隆方法被克隆。为了了解细胞衰老和有机体衰老之间的联系，我们研究了SIRTs，这是酵母/蠕虫长寿基因Sir-2编码NAD依赖性蛋白脱乙酰酶的人类同源物。我们的数据表明，与酵母或蠕虫相比，人类衰老过程的调控更复杂，并且人类SIRT蛋白在不同细胞位置（即，细胞核、核仁、细胞质和线粒体）。我们已经发现，DNA双链断裂（DSB）积累在哺乳动物细胞在细胞衰老和在体内老化，提供重要的洞察细胞衰老的机制，有助于有机体衰老。我们还在研究各种局部或系统性条件（例如，缺氧、氧化应激、肥胖、卡路里摄入）影响上述途径/因子以调节人类衰老和致癌过程。

Aging is a major risk factor of human cancers. Our project is to elucidate molecular mechanisms of aging and cancer using cellular and animal models. We have shown that normal human cells have telomerase-dependent and independent pathways for cellular senescence, which both serve as a tumor suppressive mechanism. The senescence genes on chromosome 3p21 (a transcriptional repressor of the telomerase hTERT gene) and chromosome 1q42.3 (which functions independently of telomerase regulation) are to be cloned by the positional and functional cloning methods. To understand a link between cellular aging and organismal aging, we study SIRTs, human homologs of the yeast/worm longevity gene Sir-2 encoding a NAD-dependent protein deacetylase. Our data suggest the more complex regulation of aging processes in humans than in yeast or worms and multiple functions of human SIRT proteins at different cellular locations (i.e., nucleus, nucleolus, cytoplasm and mitochondria). We have found that DNA double-strand breaks (DSB) accumulate in mammalian cells during both cellular senescence and in vivo aging, providing important insight into the mechanism by which cellular senescence contribute to organismal aging. We are also examining how various local or systemic conditions (e.g., hypoxia, oxidative stress, obesity, calorie intake) affect the above-mentioned pathways/factors to regulate human aging and carcinogenesis processes.