| Abstract: |
The effect of overexpression of p21(waf1) on drug sensitivity was studied in an osteosarcoma cell line (SaOs-2) lacking both p53 and functional retinoblastoma protein using a tetracycline (TC)-inducible expression system. p21(waf1) expression was barely detectable in SaOS-2 cells incubated in the presence of TC. After TC withdrawal, high levels of p21(waf1) were induced in these cells. These p21(waf1)-induced cells showed increased sensitivity to doxorubicin, tomudex, and methotrexate as compared to uninduced cells; this condition is associated with increased apoptosis. Expression of p21(waf1) reduced cyclin A-associated kinase activity and, surprisingly, resulted in inhibition of phosphorylation of E2F-1 and increased E2F-1 binding activity. An S-G2 cell cycle arrest/delay and an increase in expression of E2F- responsive genes (dihydrofolate reductase and thymidylate synthase) was correspondingly observed. Overexpression of p21(waf1) in cells lacking functional retinoblastoma protein may mediate sensitivity to anticancer drugs by inhibiting E2F-1 phosphorylation, which may contribute to increased S-G2 cell cycle delay and increased cell susceptibility to apoptosis. |
| Keywords: |
osteosarcoma; protein expression; protein phosphorylation; carrier protein; dna binding protein; human cell; genetics; dna-binding proteins; doxorubicin; methotrexate; cell cycle protein; metabolism; cell cycle proteins; dna damage; cell cycle; cell cycle s phase; gene overexpression; apoptosis; gene expression; antimetabolites, antineoplastic; transcription factor; cytotoxicity; tumor cells, cultured; phosphorylation; physiology; transcription factors; gene expression regulation; tumor suppressor gene; gene expression regulation, neoplastic; antiinfective agent; anti-bacterial agents; cell culture; transcription factor e2f; carrier proteins; immunoblotting; cell cycle g2 phase; cyclin dependent kinase inhibitor 1a; cyclin-dependent kinase inhibitor p21; cycline; antibiotics, antineoplastic; dihydrofolate reductase; thymidylate synthase; tetrahydrofolate dehydrogenase; quinazolines; cyclin-dependent kinases; cyclins; cyclin a; cyclin dependent kinase; antineoplastic antibiotic; antineoplastic antimetabolite; tetracycline; retinoblastoma protein; protein p21; drug sensitivity; quinazoline derivative; transcription factor e2f1; cdkn1a protein, human; genes, p53; osteosarcoma cell; dna fragment; thiophene derivative; thiophenes; raltitrexed; transcription factor dp1; e2f1 transcription factor; retinoblastoma binding protein 1; e2f transcription factors; humans; human; priority journal; article; e2f1 protein, human
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