The factors that cause cancer, a major health problem of the elderly, are still elusive. We are addressing this problem by studying molecular mechanisms of aging and cancer using cellular models. We have shown that, by means of microcell-mediated chromosome transfer, normal cells have telomerase-dependent and telomerase-independent pathways for cellular senescence, which both serve as a tumor suppressive mechanism in humans. The senescence gene on chromosome 3p21 functions through the transcriptional repression of the hTERT gene (encoding the telomerase catalytic subunit). We have identified a cis-element within the hTERT promoter region responsible for the repression, and a protein factor binding to this element is currently under investigation. A senescence gene on chromosome 1q42, which acts independently of telomerase regulation, is also 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 protein deacetylase, and Hic-5, a LIM domain protein that may play a role in commitment to cellular senescence. In addition to analyses of these specific genes, our projects include: aging-associated changes in global gene expression, which may involve chromatin structure regulated by histone modifications; and a role of DNA damage (e.g., double strand breaks and oxidative damage) in aging.
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