Overexpression of p21(waf1) decreases G(2)-M arrest and apoptosis induced by paclitaxel in human sarcoma cells lacking both p53 and functional Rb protein Journal Article
| Authors: | Li, W.; Fan, J.; Banerjee, D.; Bertino, J. R. |
| Article Title: | Overexpression of p21(waf1) decreases G(2)-M arrest and apoptosis induced by paclitaxel in human sarcoma cells lacking both p53 and functional Rb protein |
| Abstract: | We examined the effect of overexpression of p21(waf1) on cytotoxicity of paclitaxel, a microtubule stabilizer, using a tetracycline-inducible expression system in human sarcoma cells (SaOs-2) that lack both functional retinoblastoma protein and p53. Under normal growth conditions, p21(waf1) is not detectable in SaOs-2 cells. Upon p21(waf1) induction by tetracycline withdrawal, we observed a reduced apoptotic response to paclitaxel with a 3- to 6-fold increase in IC50 values compared with that of cells not induced by p21(waf1). We also observed a 5-fold increase in the IC50 value when cytotoxicity to vincristine, another microtubule-disrupting agent, was assessed, whereas we observed a marked decrease in the IC50 value after p21(waf1) induction in response to etoposide, a topoisomerase II inhibitor. After treatment with paclitaxel, less accumulation of G2-M was observed in p21(waf1)-induced cells compared with non-p21(waf1)-induced cells (57% versus 74%). p21(waf1) induction also inhibited the increased cyclin B1-associated kinase activity induced by paclitaxel. Overexpression of p21(waf1) in SaOs-2 cells lacking both p53 and functional retinoblastoma protein may decrease the G2-M arrest induced by paclitaxel due to suppression of the S-G2 checkpoint, resulting in a decreased apoptotic response of cells to paclitaxel. |
| Keywords: | osteosarcoma; controlled study; human cell; paclitaxel; mitosis; cell cycle; gene overexpression; apoptosis; etoposide; antineoplastic agents, phytogenic; vincristine; cytotoxicity; drug resistance, neoplasm; tumor cells, cultured; enzyme activity; protein p53; drug response; protein induction; tumor suppressor protein p53; cell cycle g2 phase; cyclin b1; cyclin-dependent kinase inhibitor p21; dna topoisomerase inhibitor; cyclins; cyclin b; tetracycline; retinoblastoma protein; microtubule; protein p21; drug sensitivity; phosphotransferase; g2 phase; sarcoma cell; cdc2 protein kinase; humans; human; priority journal; article |
| Journal Title: | Molecular Pharmacology |
| Volume: | 55 |
| Issue: | 6 |
| ISSN: | 0026-895X |
| Publisher: | The American Society for Pharmacology and Experimental Therapeutics |
| Date Published: | 1999-06-01 |
| Start Page: | 1088 |
| End Page: | 1093 |
| Language: | English |
| PUBMED: | 10347252 |
| PROVIDER: | scopus |
| DOI: | 10.1124/mol.55.6.1088 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
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