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Overexpression of p21(waf1) leads to increased inhibition of E2F-1 phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells

Li, WW; Fan, JG; Hochhauser, D; Bertino, JR; (1997) Overexpression of p21(waf1) leads to increased inhibition of E2F-1 phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells. CANCER RES , 57 (11) 2193 - 2199.

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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-G(2) 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-G(2) cell cycle delay and increased cell susceptibility to apoptosis.

Type: Article
Title: Overexpression of p21(waf1) leads to increased inhibition of E2F-1 phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells
Keywords: DEPENDENT KINASE-ACTIVITY, S-PHASE ENTRY, TRANSCRIPTION FACTOR, DNA-SYNTHESIS, G(1) ARREST, P53 GENE, IN-VIVO, APOPTOSIS, PROTEIN, P21
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/67583
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