Inhibition of the cyclin D1/E2F pathway by PCA-4230, a potent repressor of cellular proliferation.

Abstract

1. Tight control of cellular growth is essential to ensure normal tissue patterning and prevent pathological responses. Excessive vascular smooth muscle cell (VSMC) proliferation is associated with the pathophysiology of atherosclerosis and restenosis post-angioplasty. Thus, drug targeting of pathological VSMC growth may be a suitable therapeutic intervention in vascular proliferative diseases. 2. In the present study, we investigated the mechanisms underlying VSMC growth arrest induced by the pharmacological agent PCA-4230. Addition of PCA-4230 to cultured VSMCs blocked the induction of cyclin D1 and cyclin A expression normally seen in serum-restimulated cells. Moreover, PCA-4230 inhibited cyclin-dependent kinase 2 (CDK2) activity and abrogated hyperphosphorylation of the retinoblastoma (Rb) gene product. Similarly, PCA-4230-dependent growth arrest of transformed cell lines correlated with reduced level of cyclin D1 protein and inhibition of CDK2 activity. Consistent with these findings, PCA-4230 repressed serum-inducible cyclin A promoter activity, and overexpression of either cyclin D1 or E2F1 efficiently circumvented this inhibitory effect. Importantly, adenovirus-mediated overexpression of E2F1 restored S-phase entry in PCA-4230-treated VSMCs, demonstrating that PCA-4230 represses cyclin A gene expression and VSMC growth via inhibition of the cyclin D1/E2F pathway. 3. Because of its ability to inhibit the growth of human VSMCs and transformed cell lines, future studies are warranted to assess whether PCA-4230 may be a suitable therapeutic intervention for the treatment of hyperproliferative disorders, including cardiovascular disease and cancer.

• Authors: D Goukassian, S M Sanz-González, I Pérez-Roger, J Font de Mora, J Ureña, V Andrés
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 132 Issue 7 Pg. 1597-605 (Apr 2001) ISSN: 0007-1188 [Print] England
• PMID: 11264255 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• Cell Cycle Proteins
• Cyclin A
• DNA-Binding Proteins
• Dihydropyridines
• E2F Transcription Factors
• E2F1 Transcription Factor
• E2F1 protein, human
• E2f1 protein, rat
• Recombinant Fusion Proteins
• Retinoblastoma-Binding Protein 1
• Transcription Factor DP1
• Transcription Factors
• PCA 4230
• Cyclin D1
• Luciferases

Topics

• Animals
• Carrier Proteins
• Cell Cycle Proteins (drug effects, metabolism)
• Cell Division (drug effects)
• Cells, Cultured
• Cyclin A (genetics)
• Cyclin D1 (metabolism, physiology)
• DNA-Binding Proteins
• Dihydropyridines (pharmacology)
• Dose-Response Relationship, Drug
• E2F Transcription Factors
• E2F1 Transcription Factor
• Humans
• Luciferases (drug effects, genetics, metabolism)
• Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
• Promoter Regions, Genetic (genetics)
• Rats
• Rats, Inbred F344
• Recombinant Fusion Proteins (drug effects, genetics, metabolism)
• Retinoblastoma-Binding Protein 1
• S Phase
• Signal Transduction (drug effects)
• Time Factors
• Transcription Factor DP1
• Transcription Factors (metabolism, physiology)
• Tumor Cells, Cultured