Transcription factor AP-1 activity is required for initiation of DNA synthesis and is lost during cellular aging.
Activation of the AP-1 complex of transcription factors is one of the earliest nuclear responses to mitogenic stimuli. We demonstrate directly that AP-1 activity is required for human cells to proliferate in response to serum. We also find that activity of the AP-1 complex is selectively reduced in old human fibroblasts prior to their entering a fully senescent state. Levels of Fos protein induced through diverse signal transduction pathways, the amount of AP-1 DNA binding activity in vitro, and the activity of an AP-1-dependent reporter gene in vivo are substantially decreased as fibroblasts age. Moreover, the composition of the AP-1 complex changes, so that old cells produce predominantly Jun-Jun homodimers instead of Fos-Jun heterodimers. Changes in AP-1 activity may be due in part to changes in posttranslational modification of Fos protein that impair its ability to form active DNA-binding heterodimers with Jun. These data suggest that changes in AP-1 activity may contribute to the inability of senescent cells to proliferate in response to mitogens.
Riabowol
K
K
Cold Spring Harbor Laboratory, NY 11724.
Schiff
J
J
Gilman
M Z
MZ
D001483:Base Sequence; D002453:Cell Cycle; D002478:Cells, Cultured; D016922:Cellular Senescence; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007526:Isoelectric Point; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic
D006133:Growth Substances; D009838:Oligodeoxyribonucleotides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun