LOSS OF SERUM RESPONSE FACTOR ACTIVITY IS THE BASIS OF REDUCED C-FOS EXPRESSION IN AGING HUMAN FIBROBLASTS

Human diploid fibroblasts undergo a limited number of population doubl ings in vitro and are used widely as a model of cellular aging. Despit e growing evidence that cellular aging occurs as a result of altered g ene expression, little is known about theactivity of transcription fac tors in aging cells. Here we report that the dramatic reduction in the expression of the transcription factor FOS during cellular aging appe ars to be due to the inability of another transcription factor, serum response factor (SRF), to bind to its cognate site termed the serum re sponse 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 prese nt evidence that hyperphosphorylation of SRF is responsible for the de creased binding activity seen in late passage cells, as proposed previ ously for the FOS protein.