CONTROL OF FIBROBLAST SENESCENCE AND ACTIVATION OF PROGRAMMED CELL-DEATH

We have characterized a nuclear phosphoprotein of 57 kda, statin, foun d only in nonproliferating cells of both quiescent and senescent natur es. Emerging results suggest that statin may function as a sequester t o block the early G1 phase phosphorylation for the RB protein. A secon d protein, terminin, undergoes senescence-specific posttranslational m odification from 90 to 60 kda, and further death-specific conversion f rom 60 to 30 kda. We also found that apoptotic mouse 3T3 fibroblasts e xpress c-fos, c-myc, c-jun, and cdc2, as well as the upregulation of R B phosphorylation and BrdU incorporation, just before final DNA fragme ntation and death. It seems that en route to death, cells re-enter the cell-cycle traverse and experience early G1 and part of S Phase; howe ver, this cycling event is an abortive one. In contrast, senescent fib roblasts are resistant to the initiation of the death program, since t hey are unable to enter cell cycle traverse. Long-term serial passagin g of normal human fibroblasts may be inadvertently selecting those, wh ile termed as senescent, are also specialized survivors, and thus a go od culture model to study both the control of permanent departure from cell cycle traverse and the mechanism underlying the survival or anti death cellular program. (C) 1994 Wiley-Liss, Inc.