title: Concentration-dependent differential effects of an epothilone analog on cell cycle and p53 signaling.
abstract: The tumor-suppressor protein p53 is considered to be one of the most important transport hubs of cell signal transduction, playing critical roles in the control of cell cycle arrest, apoptosis and many other processes as a nuclear transcription factor. p53 also acts in the cytoplasm to trigger apoptosis. Paclitaxel and other microtubule inhibitors can inhibit the growth of different types of cancer cells and induce apoptosis which is believed to be p53-independent. In the present study, we demonstrated that UTD1, a genetically engineered epothilone analog and a new microtubule inhibitor, activated p53 as a transcription factor at low concentrations demonstrated by its enhanced transcriptional activity and accumulation of p21, which led to cell cycle arrest. However, at high concentrations of UTD1, p53 was accumulated in the cytoplasm which contributed to induction of apoptosis. These observations indicate that the epothilone analog has differential effects on intracellular signaling and implies that p53 plays different roles in cells exposed to different concentrations of the anticancer agent.
authors.affiliation: Research Center for Molecular Medicine, Dalian University of Technology, Dalian, Liaoning 116023, P.R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: An
authors.affiliation: Research Center for Molecular Medicine, Dalian University of Technology, Dalian, Liaoning 116023, P.R. China.
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Zhao
authors.affiliation: Research Center for Molecular Medicine, Dalian University of Technology, Dalian, Liaoning 116023, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.affiliation: Research Center for Molecular Medicine, Dalian University of Technology, Dalian, Liaoning 116023, P.R. China.
authors.forename: Rong-Guo
authors.initials: RG
authors.lastname: Qiu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D034261:Epothilones / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D017239:Paclitaxel / Q000008:administration & dosage; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D034261:Epothilones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel