Cellular senescence, or terminal loss of proliferative potential, has been well documented to occur in normal human cells serially subcultured in vitro. Cell fusion studies have demonstrated that the phenotype of senescence is dominant over that of immortality, and additional cell fusions, involving immortal human cells, have defined four complementation groups for indefinite division. Microcell fusion approaches have identified the presence of cell senescence genes related to groups B, C and D, on chromosomes 4, 1 and 7, respectively. More recently, using antibodies against the protein mortalin, immunostaining patterns have been found to distinguish normal from immortal cells, as well as identify the complementation group to which the immortal cell assigns. Interestingly, the mortalin pattern returns to that of a normal cell in microcell hybrids that exhibit loss of proliferation following the introduction of human chromosomes 1 and 7, into immortal cells assigned to groups C and D, respectively. (We have not yet studied microcell hybrids obtained from the introduction of human chromosome 4 into immortal cells assigned to group B).
The aims of this proposal are therefore to determine whether localization in a particular subcellular compartment is responsible for this difference in staining, and the molecular mechanisms that result in the differential staining observed. The results will increase our understanding of the mechanisms involved in cellular senescence and immortalization.
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