title: Mitomycin C and doxorubicin elicit conflicting signals by causing accumulation             of cyclin E prior to p21WAF1/CIP1 elevation in human hepatocellular carcinoma             cells.
abstract: Proteins involved in the G1 phase of the cell cycle are aberrantly expressed,             sometimes in mutated forms, in human cancers including human hepatocellular carcinoma.             Upon attack by a DNA-damaging anticancer drug, a cell arrests at the G1 phase;             this is a safety feature prohibiting entry of DNA-damaged cells into S-phase.             p21WAF1/CIP1 prevents damaged cells from progressing to the next cell cycle. Here,             we show that, in response to mitomycin C and doxorubicin, human hepatocellular             carcinoma cells generate conflicting signals, mediated by cyclin E and p21WAF1/CIP1,             which respectively accelerates and represses cell cycle transition. Exposure to             these anticancer drugs led to rapid accumulation of cyclin E in both p53-proficient             HepG2 and p53-deficient Hep3B cells. Such anticancer drug-induced cyclin E accumulation             influenced the G1-S-phase transition, but not DNA fragmentation-mediated death.             In p53-proficient HepG2 cells, accumulation of cyclin E was followed by an increase             in the level of p53-dependent p21WAF1/CIP1, thereby inhibiting further the G1-S-phase             transition. Sublethal drug concentrations also induced rapid accumulation of cyclin             E, but p21WAF1/CIP1 accumulation was delayed, further facilitating the G1-S-phase             transition. Eventually, most cells arrested in G2/M. Thus, mitomycin C- or doxorubicin-induced             conflicting signals, mediated by cyclin E and p21WAF1/CIP1, are in play in human             hepatocellular carcinoma cells. Damaged G1 cells either immediately enter S-phase,             or do not do so at all, depending on the extent of DNA damage.
authors: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors: Sun-Young
authors: SY
authors: Choi
authors: Yan Nan
authors: YN
authors: Shen
authors: Seon Rang
authors: SR
authors: Woo
authors: Miyoung
authors: M
authors: Yun
authors: Jeong-Eun
authors: JE
authors: Park
authors: Yeun-Jin
authors: YJ
authors: Ju
authors: Jaemin
authors: J
authors: Jeong
authors: Hyun-Jin
authors: HJ
authors: Shin
authors: Hyun-Yoo
authors: HY
authors: Joo
authors: Eun-Ran
authors: ER
authors: Park
authors: Jung-Kee
authors: JK
authors: Lee
authors: Sang Hoon
authors: SH
authors: Kim
authors: Myung-Haing
authors: MH
authors: Cho
authors: In-Soo
authors: IS
authors: Kong
authors: Kee-Ho
authors: KH
authors: Lee
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019927:Cyclin E / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D016193:G1 Phase / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016685:Mitomycin / Q000008:administration & dosage; D016196:S Phase / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D004317:Doxorubicin