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

Abstract

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.

• Authors: Jason Savell, Yihong Ma, Kristin S Morrow, Richard Jove, Nancy Olashaw, Pope L Moseley, W Douglas Cress, Walker Wharton
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 2 Pg. 205-13 (Feb 2004) ISSN: 1535-7163 [Print] United States
• PMID: 14985461 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cell Cycle Proteins
• Cyclin A
• DNA-Binding Proteins
• E2F Transcription Factors
• E2F1 Transcription Factor
• E2f1 protein, mouse
• Mitogens
• Proto-Oncogene Proteins
• Retinoblastoma Protein
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• Stat1 protein, mouse
• Stat3 protein, mouse
• Trans-Activators
• Transcription Factors
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• Cdk4 protein, mouse
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinases

Topics

• Animals
• BALB 3T3 Cells
• Cell Cycle Proteins (genetics, metabolism)
• Cyclin A (metabolism)
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinases (antagonists & inhibitors, metabolism)
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• E2F Transcription Factors
• E2F1 Transcription Factor
• Electrophoretic Mobility Shift Assay
• G1 Phase (drug effects)
• Gene Expression Regulation (drug effects)
• Mice
• Mitogens (antagonists & inhibitors, pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Retinoblastoma Protein (metabolism)
• S Phase (drug effects)
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• Trans-Activators (antagonists & inhibitors, metabolism)
• Transcription Factors (genetics, metabolism)
• Transfection
• Tyrphostins (pharmacology)