Human diploid fibroblasts undergo a limited number of population doublings in vitro and are used widely as a model of cellular aging. Despite growing evidence that cellular aging occurs as a result of altered gene expression, little is known about the activity of transcription factors in aging cells. Here we report that the dramatic reduction in the expression of the transcription factor FOS during cellular aging appears to be due to the inability of another transcription factor, serum response factor (SRF), to bind to its cognate site termed the serum response element (SRE) that is found upstream of several genes including the human c-fos gene. In contrast, the activities of proteins binding to the RNA polymerase “core” element TATA and to the cAMP response element (CRE) were maintained in senescing human fibroblasts. We present evidence that hyperphosphorylation of SRF is responsible for the decreased binding activity seen in late passage cells, as proposed previously for the FOS protein.
