Modulation of cyclin gene expression by adenovirus E1A in a cell line with E1A-dependent conditional proliferation.
To investigate how adenovirus E1A controls cell proliferation, we have fused E1A to the hormone-binding domain of the human estrogen receptor (ER) and introduced the E1A-ER chimeric gene together with an activated ras gene into primary rat embryo fibroblasts. Cell lines derived from this transfection proliferate in an estrogen-dependent manner. Estrogen-dependent activation of E1A-ER led to a rapid induction of both cyclin E and cyclin A gene expression. In contrast, levels of cyclin D1 were strongly reduced by activation of E1A-ER. Similar changes in cyclin gene expression were observed when primary human fibroblasts were infected with wild-type adenovirus and when adenovirus E1A was stably expressed in NIH 3T3 cells. Our findings suggest that activation of cyclin A and E, but not D1, gene expression by E1A precedes and may be responsible for E1A-dependent cell proliferation. In contrast, we found that quantitative disruption of complexes between the E2F transcription factor and the retinoblastoma protein is not required for E1A-dependent S-phase entry.
Spitkovsky
D
D
Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Steiner
P
P
Lukas
J
J
Lees
E
E
Pagano
M
M
Schulze
A
A
Joswig
S
S
Picard
D
D
Tommasino
M
M
Eilers
M
M
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D019938:Cyclin D1; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004967:Estrogens / Q000494:pharmacology*; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000187:drug effects*; D011905:Genes, ras / Q000235:genetics; D046911:Macromolecular Substances; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000187:drug effects; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D017500:Adenovirus E1A Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004967:Estrogens; D046911:Macromolecular Substances; D015513:Oncogene Proteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019938:Cyclin D1