Transcription Factor AP-1 Activity is Required for Initiation of DNA Synthesis and is Lost During Cellular Aging

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 89; no. 1; pp. 157 - 161
• Main Authors: Riabowol, Karl, Schiff, Jonathan, Gilman, Michael Z.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.01.1992; National Acad Sciences; National Academy of Sciences
• Subjects: 550201 - Biochemistry- Tracer Techniques; AMINO ACIDS; ANIMAL CELLS; ANIMALS; Antibodies; AUTORADIOGRAPHY; Base Sequence; BASIC BIOLOGICAL SCIENCES; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; BIOCHEMISTRY; Biological and medical sciences; CARBOXYLIC ACIDS; Cell Cycle; Cell growth; Cell lines; Cell nucleus; CELL PROLIFERATION; Cells; Cells, Cultured; Cellular biology; Cellular Senescence; CHEMISTRY; CONNECTIVE TISSUE CELLS; CYTOCHEMISTRY; DAYS LIVING RADIOISOTOPES; Deoxyribonucleic acid; DNA; DNA REPLICATION; DRUGS; ENZYME ACTIVITY; EVEN-ODD NUCLEI; FIBROBLASTS; Fundamental and applied biological sciences. Psychology; Growth Substances - pharmacology; Humans; Isoelectric Point; ISOTOPES; LIGHT NUCLEI; LIPOTROPIC FACTORS; MAMMALS; MAN; Medical research; MEMBRANE PROTEINS; METABOLIC ACTIVATION; METHIONINE; Molecular and cellular biology; MOLECULAR BIOLOGY; Molecular genetics; Molecular Sequence Data; NUCLEI; NUCLEIC ACID REPLICATION; NUCLEOPROTEINS; Oligodeoxyribonucleotides - chemistry; Oligonucleotides; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANIC SULFUR COMPOUNDS; PRIMATES; Protein isoforms; PROTEINS; Proto-Oncogene Proteins c-fos - chemistry; Proto-Oncogene Proteins c-fos - physiology; Proto-Oncogene Proteins c-jun - physiology; RADIOISOTOPES; RECEPTORS; Regulatory Sequences, Nucleic Acid; SOMATIC CELLS; SULFUR 35; SULFUR ISOTOPES; TRANSCRIPTION FACTORS; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing; VERTEBRATES; Human; Cell line; Cell death; Gene product; C-Onc gene; DNA synthesis; Transcription factor; Fibroblast
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.1.157

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.