14985461

pubmed:Citation

2

AG490, a member of the tryphostin family of protein kinase inhibitors, repressed G(0)-G(1) traverse in BALB/c-3T3 cells. While the early induction of STAT activity was repressed by AG490, extracellular signal-regulated kinase (ERK) activation was unaffected and a pattern of gene expression suggested that cells exited G(0) in the presence of the inhibitor. Although AG490 did not alter the induction of cyclin D1 protein, neither cyclin D1- nor cyclin D3-associated kinase activity was observed in growth-inhibited cells. Surprisingly, p130 was partially phosphorylated, and E2F3A protein was expressed in mitogen-stimulated AG490-treated cells despite the lack of cyclin D-associated kinase activity. These data suggest that AG490 inhibits a cellular pathway required for mid-G(0)-G(1) traverse that is located after the induction of early processes potentially mediated by E2F (although independent of cyclin D-associated kinase activity) but before the late G(1) increase in E2F-dependent transcription. Infection of AG490-treated cells with an E2F-1 adenovirus caused the induction of cyclin A, but could not overcome the drug-induced cell cycle arrest that was coincident with the repression of cyclin-dependent kinase 2 (cdk2)-associated kinase activation. We conclude that cdk2-associated kinase activity is modulated by a cellular process repressed by AG490. Furthermore, this cdk2-associated kinase activity is required for G(0)-G(1) traverse in some role other than the regulation of E2F-dependent transcription.

eng

IM

MEDLINE

1535-7163

Print

NLM

205-13

pubmed-meshheading:14985461-Animals, pubmed-meshheading:14985461-BALB 3T3 Cells, pubmed-meshheading:14985461-Cell Cycle Proteins, pubmed-meshheading:14985461-Cyclin A, pubmed-meshheading:14985461-Cyclin-Dependent Kinase 4, pubmed-meshheading:14985461-Cyclin-Dependent Kinases, pubmed-meshheading:14985461-DNA-Binding Proteins, pubmed-meshheading:14985461-E2F Transcription Factors, pubmed-meshheading:14985461-E2F1 Transcription Factor, pubmed-meshheading:14985461-Electrophoretic Mobility Shift Assay, pubmed-meshheading:14985461-G1 Phase, pubmed-meshheading:14985461-Gene Expression Regulation, pubmed-meshheading:14985461-Mice, pubmed-meshheading:14985461-Mitogens, pubmed-meshheading:14985461-Proto-Oncogene Proteins, pubmed-meshheading:14985461-Retinoblastoma Protein, pubmed-meshheading:14985461-S Phase, pubmed-meshheading:14985461-STAT1 Transcription Factor, pubmed-meshheading:14985461-STAT3 Transcription Factor, pubmed-meshheading:14985461-Trans-Activators, pubmed-meshheading:14985461-Transcription Factors, pubmed-meshheading:14985461-Transfection, pubmed-meshheading:14985461-Tyrphostins

AG490 inhibits G1-S traverse in BALB/c-3T3 cells following either mitogenic stimulation or exogenous expression of E2F-1.

Journal Article, Research Support, U.S. Gov't, P.H.S.