REGULATION OF C-FOS EXPRESSION IN SENESCING WERNER SYNDROME FIBROBLASTS DIFFERS FROM THAT OBSERVED IN SENESCING FIBROBLASTS FROM NORMAL DONORS

The Werner syndrome (WS) is a segmental progeroid syndrome caused by a recessive mutation (WRN) mapped to 8p12. The replicative life spans o f somatic cells cultured from WS patients are substantially reduced co mpared to age-matched controls. Certain molecular concomitants of the replicative decline of normal fibroblast cultures have recently been d efined, and it appears that multiple changes in gene expression accomp any normal cell senescence. If the mechanisms by which WS cells exit t he cell cycle were entirely comparable, the molecular markers of senes cence should be identical in normal and WS cells. We find that this is not the case. The constitutive expression of statin, a nuclear protei n associated with the nonproliferating state, was comparably expressed in normal and WS senescent cells. Likewise, the steady state levels o f p53, a protein known to be involved in the G1 checkpoint of the cell cycle, were similar in early-passage fibroblasts from normal and WS s ubjects. The levels of p53 were not increased in senescent fibroblasts , whether derived from normal or WS subjects. By contrast, the inducib ility of mRNA and protein expression of the c-fos protooncogene is pre served in late-passage WS cells. This is in contrast to what is observ ed in late-passage fibroblasts from normal subjects. Additional genoty pes will have to be examined, however, to determine the specificity of this new aspect of the WS phenotype. (C) 1995 Wiley-Liss, Inc.