Inhibition of the cyclin D1/E2F pathway by PCA-4230, a potent repressor of cellular proliferation
| Autor: | Goukassian D, Sanz-González SM, Pérez-Roger I, Font de Mora J, Ureña J, Andrés V |
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| Rok vydání: | 2001 |
| Předmět: |
Dihydropyridines
Time Factors Recombinant Fusion Proteins Cell Cycle Proteins Cyclin A Muscle Smooth Vascular S Phase Tumor Cells Cultured Animals Humans Cyclin D1 Luciferases Promoter Regions Genetic Cells Cultured Dose-Response Relationship Drug Rats Inbred F344 E2F Transcription Factors Rats DNA-Binding Proteins Papers Carrier Proteins Transcription Factor DP1 Cell Division E2F1 Transcription Factor Retinoblastoma-Binding Protein 1 Signal Transduction Transcription Factors |
| Zdroj: | BRITISH JOURNAL OF PHARMACOLOGY r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname |
| ISSN: | 0007-1188 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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