The roots of cellular mortality-limited capacity of normal cells to di
vide, and immortalization-unabated proliferation of cancerous cells re
main undefined so far. Out of a variety of experimental strategies emp
loyed, the cell fusion approach has been proven to be significantly in
formative. The present article reviews some of the more important rece
nt results and describes the use of natural and conditional aging syst
ems obtained by the fusion of mortal and immortal mouse fibroblasts to
identify putative senescence-determining and/or senescence-escaping g
enes. The strategy has led to the isolation of a novel 66-kDa protein,
mortalin- a unique member of the mouse heat shock protein 70 (hsp 70)
family. The intracellular distributions of mortalin, i.e., cytosolic
and perinuclear, distinguish the mortal phenotype from the immortal on
e, respectively. Consistently, the cytosolic mortalin is seen to have
a senescence-inducing function in contrast to the perinuclear mortalin
which has no detectable effect on cellular phenotype. It is suggested
that mortalin can be exploited to unravel some aspects of cellular mo
rtality and immortality and also for the early detection of cancerous
cells.