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 of somatic cells cultured from WS patients are substantially reduced compared to age-matched controls. Certain molecular concomitants of the replicative decline of normal fibroblast cultures have recently been defined, and it appears that multiple changes in gene expression accompany normal cell senescence. If the mechanisms by which WS cells exit the cell cycle were entirely comparable, the molecular markers of senescence should be identical in normal and WS cells. We find that this is not the case. The constitutive expression of statin, a nuclear protein associated with the nonproliferating state, was comparably expressed in normal and WS senescent cells. Likewise, the steady state levels of 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 subjects. The levels of p53 were not increased in senescent fibroblasts, whether derived from normal or WS subjects. By contrast, the inducibility of mRNA and protein expression of the c-fos protooncogene is preserved in late-passage WS cells. This is in contrast to what is observed in late-passage fibroblasts from normal subjects. Additional genotypes will have to be examined, however, to determine the specificity of this new aspect of the WS phenotype.
Oshima
J
J
Department of Pathology, University of Washington, Seattle 98195.
Campisi
J
J
Tannock
T C
TC
Martin
G M
GM
D000328:Adult; D015415:Biomarkers; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008875:Middle Aged; D020648:Peptide Elongation Factor 1; D014176:Protein Biosynthesis; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014898:Werner Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D015415:Biomarkers; D018797:Cell Cycle Proteins; C503234:EEF1A2 protein, human; D020648:Peptide Elongation Factor 1; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53