Cell Senescence, Carcinogenesis, and Aging

细胞衰老、癌变和衰老

• 批准号: 7291786
• 负责人: james barrett
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7291786
• 关键词: Cell; Senescence; Carcinogenesis; Aging

Aging is a major risk factor of human cancers. Our project was to elucidate molecular mechanisms of aging and cancer using cellular and animal models. We showed 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) could not be cloned in our laboratory. To understand a link between cellular aging and organismal aging, we studied SIRTs, human homologs of the yeast/worm longevity gene Sir-2 encoding a NAD-dependent protein deacetylase. Our data suggested 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). It was also suggested that various local or systemic conditions (e.g., hypoxia, oxidative stress, obesity and calorie intake) could affect cellular senescence, telomerase regulation and SIRT protein function to modulate human aging and carcinogenesis processes.

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。我们发现正常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3p21（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）上的衰老基因无法在我们的实验室中克隆。为了了解细胞衰老和有机体衰老之间的联系，我们研究了 SIRT，即编码 NAD 依赖性蛋白脱乙酰酶的酵母/蠕虫长寿基因 Sir-2 的人类同源物。我们的数据表明，人类衰老过程的调节比酵母或蠕虫更复杂，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）具有多种功能。研究还表明，各种局部或全身条件（例如缺氧、氧化应激、肥胖和热量摄入）可能影响细胞衰老、端粒酶调节和 SIRT 蛋白功能，从而调节人类衰老和癌变过程。

项目成果

Immortalization of normal human embryonic fibroblasts by introduction of either the human papillomavirus type 16 E6 or E7 gene alone.

通过单独引入人乳头瘤病毒 16 型 E6 或 E7 基因，使正常人胚胎成纤维细胞永生化。

• DOI: 10.1002/ijc.11219
• 发表时间: 2003
• 期刊: International journal of cancer. Journal international du cancer
• 作者: Yamamoto,Akito;Kumakura,Shin-ichi;Uchida,Minoru;Barrett,JCarl;Tsutsui,Takeki
• 通讯作者: Tsutsui,Takeki

Candidate chromosomal regions for genes involved in activation of alternative lengthening of telomeres in human immortal cell lines.

参与人类永生细胞系中端粒选择性延长激活的基因的候选染色体区域。

• DOI: 10.1016/s0531-5565(03)00072-x
• 发表时间: 2003
• 期刊: Experimental gerontology
• 影响因子: 3.9
• 作者: Shigeeda,Nobumasa;Uchida,Minoru;Barrett,JCarl;Tsutsui,Takeki
• 通讯作者: Tsutsui,Takeki

Identification of a </= 600-kb region on human chromosome 1q42.3 inducing cellular senescence.

人类染色体 1q42.3 上 </= 600-kb 区域的鉴定可诱导细胞衰老。

• DOI: 10.1038/sj.onc.1206143
• 发表时间: 2003
• 期刊: Oncogene
• 影响因子: 8
• 作者: Yawata,Toshio;Kamino,Hiroki;Kugoh,Hiroyuki;Katoh,Motonobu;Nomura,Nobuo;Oishi,Michio;Horikawa,Izumi;Barrett,JCarl;Oshimura,Mitsuo
• 通讯作者: Oshimura,Mitsuo

Role of Ets/Id proteins for telomerase regulation in human cancer cells.

• DOI: 10.1016/s0014-4800(03)00092-3
• 发表时间: 2003-12
• 期刊: Experimental and molecular pathology
• 影响因子: 3.6
• 作者: Xiaodong Xiao;M. Athanasiou;I. Sidorov;I. Horikawa;Gina H Cremona;D. Blair;J. Barret;D. Dimitrov

Immortal, telomerase-negative cell lines derived from a Li-Fraumeni syndrome patient exhibit telomere length variability and chromosomal and minisatellite instabilities.

来自李法美尼综合征患者的永生端粒酶阴性细胞系表现出端粒长度变异性以及染色体和小卫星不稳定性。

• DOI: 10.1093/carcin/bgg024
• 发表时间: 2003
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Tsutsui,Takeki;Kumakura,Shin-Ichi;Tamura,Yukiko;Tsutsui,TakeoW;Sekiguchi,Mizuki;Higuchi,Tokihiro;Barrett,JCarl
• 通讯作者: Barrett,JCarl