Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010417-06
Application #
7291786
Study Section
(LBC)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2005
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Sedelnikova, Olga A; Horikawa, Izumi; Zimonjic, Drazen B et al. (2004) Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol 6:168-70
Li, Shuanfang; Hursting, Stephen D; Davis, Barbara J et al. (2003) Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann N Y Acad Sci 983:161-9
Li, Shuanfang; Hansman, Roberta; Newbold, Retha et al. (2003) Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog 38:78-84
Xiao, Xiaodong; Athanasiou, Meropi; Sidorov, Igor A et al. (2003) Role of Ets/Id proteins for telomerase regulation in human cancer cells. Exp Mol Pathol 75:238-47
Tsutsui, Takeki; Kumakura, Shin-Ichi; Tamura, Yukiko et al. (2003) Immortal, telomerase-negative cell lines derived from a Li-Fraumeni syndrome patient exhibit telomere length variability and chromosomal and minisatellite instabilities. Carcinogenesis 24:953-65
Burroughs, Kevin D; Oh, Jennifer; Barrett, J Carl et al. (2003) Phosphatidylinositol 3-kinase and mek1/2 are necessary for insulin-like growth factor-I-induced vascular endothelial growth factor synthesis in prostate epithelial cells: a role for hypoxia-inducible factor-1? Mol Cancer Res 1:312-22
Tsutsui, Takeki; Tamura, Yukiko; Yagi, Eiichi et al. (2003) Cell-transforming activity and mutagenicity of 5 phytoestrogens in cultured mammalian cells. Int J Cancer 105:312-20
Horikawa, Izumi; Barrett, J Carl (2003) Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms. Carcinogenesis 24:1167-76
Shigeeda, Nobumasa; Uchida, Minoru; Barrett, J Carl et al. (2003) Candidate chromosomal regions for genes involved in activation of alternative lengthening of telomeres in human immortal cell lines. Exp Gerontol 38:641-51
Kenney, Nicholas J; Bowman, Arthur; Korach, Kenneth S et al. (2003) Effect of exogenous epidermal-like growth factors on mammary gland development and differentiation in the estrogen receptor-alpha knockout (ERKO) mouse. Breast Cancer Res Treat 79:161-73

Showing the most recent 10 out of 14 publications