Ageing/CancerDate Added: 6/15/2004 10:49:00 AM
Last Updated: 6/15/2004 10:49:00 AM
Description of projects available to graduate students:
Most cells cannot divide indefinitely due to a process termed cellular senescence. Cellular senescence appears to be a fundamental feature of somatic cells, with the exception of most tumor cells and certain stem cells. It is well accepted that cellular senescence is a powerful tumor suppressive mechanism. In fact, cancer cells escape cellular senescence in order to proliferate and eventually form tumors. Since a number of molecular changes that are observed in senescent cells occurs in somatic cells during the ageing process, investigating the molecular mechanisms underlying cellular senescence, will also allow us to better understand the more complicated ageing process. Thus, it appears that ageing is the price we have to pay to avoid cancer. Molecules that promote cellular senescence represent potential therapeutic targets in the fight against cancer, and key player during the ageing process.Our laboratory has been investigating the role of caveolin-1, a caveolin isoform that is expressed in most cell types with the exception of striated muscle cells, in cellular senescence and cancer. Senescent human diploid fibroblasts have been shown to express higher levels of caveolin-1, as compared to younger human diploid fibroblasts. We have recently generated caveolin-1 transgenic mice. Interestingly, mouse embryonic fibroblasts over-expressing caveolin-1, derived from this mouse model, display a premature senescent phenotype. Taken together, these results indicate that caveolin-1 may have a central role in the signaling events that lead to cellular senescence. As a consequence, caveolin-1 may possess tumor suppressor properties. Several independent data support the idea that caveolin-1 is a tumor suppressor protein: i) caveolin-1 expression is down-regulated in a variety of human cancers; ii) down-regulation of caveolin-1 is sufficient to transform fibroblasts in culture; iii) the caveolin-1 gene is localized to a suspected tumor suppressor locus (D7S522; 7q31.1), a known fragile site (FRA7G) that is deleted in many types of cancer; iv) a common sporadic mutation in the caveolin-1 gene has been identify in human breast cancer patients; e) loss of caveolin-1 expression leads to mammary epithelial cell hyperplasia in normal mice, and accelerates the development of dysplastic mammary lesions in tumor-prone transgenic mice. We are currently investigating the hypothesis that caveolin-1 is a key player in the signal transduction events that lead to cellular senescence. These investigations will contribute to elucidate the molecular mechanisms underlying ageing and cancerous cell transformation.
Techniques graduate student will learn:
The laboratory is set up to conduct experiments that employ cellular and molecular biology techniques, including: Southern Blotting, Northern Blotting, PCR, DNA cloning, Western blotting, Immunoprecipitation analysis, Cell Culture, Transient and Stable Transfections, Confocal Microscopy, Transgenic and knock-out mice technologies.
Molecular Genetics and Developmental Biology
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