THE PATHWAY OF CELL SENESCENCE - WI-38 CELLS ARREST IN LATE G(1) AND ARE UNABLE TO TRAVERSE THE CELL-CYCLE FROM A TRUE G(0) STATE

Senescent human diploid fibroblasts have an undefined arrest state par tially characterized by the differential expression of cell cycle-regu lated genes and a failure to complete the mitogen-stimulated cascade o f signalling events that lead to DNA synthesis. We present evidence th at this arrest state precludes the entry of senescent fibroblasts into a normally reversible G(0) or quiescent state. Both nuclear associati on kinetics and quinacrine dihydrochloride nuclear fluorescence show c hromatin condensation patterns consistent with arrest in late G(1) and exclusion of senescent cells from the G(0) phase of the cell cycle. S teady-state thymidine kinase mRNA levels indicate that some of the sig nalling cascades initiated from a functional G(0) state may be intact in senescent cells, at least qualitatively, and that this expression m ay represent an abortive attempt to complete pathways required for DNA replication. Taken together, the evidence suggests that growth arrest in senescent cells likely occurs in a physiologic state fundamentally distinct from that of the G(0), quiescent state that is achieved by n onproliferating young cells. A full response to serum or growth factor addition, leading from quiescence to DNA synthesis, may require cells to initiate this traverse from a true G(0) state. If so, senescent ce lls would be excluded from this pathway. (C) 1998 Elsevier Science Inc .