title: Role of activating transcription factor 3 on TAp73 stability and apoptosis in paclitaxel-treated cervical cancer cells.
abstract: Taxol (paclitaxel) is a potent anticancer drug that has been found to be effective against several tumor types, including cervical cancer. However, the exact mechanism underlying the antitumor effects of paclitaxel is poorly understood. Here, paclitaxel induced the apoptosis of cervical cancer HeLa cells and correlated with the enhanced activation of caspase-3 and TAp73, which was strongly inhibited by TAp73beta small interfering RNA (siRNA). In wild-type activating transcription factor 3 (ATF3)-overexpressed cells, paclitaxel enhanced apoptosis through increased alpha and beta isoform expression of TAp73; however, these events were attenuated in cells containing inactive COOH-terminal-deleted ATF3 [ATF3(DeltaC)] or ATF3 siRNA. In contrast, paclitaxel-induced ATF3 expression did not change in TAp73beta-overexpressed or TAp73beta siRNA-cotransfected cells. Furthermore, paclitaxel-induced ATF3 translocated into the nucleus where TAp73beta is expressed, but not in ATF3(DeltaC) or TAp73beta siRNA-transfected cells. As confirmed by the GST pull-down assay, ATF3 bound to the DNA-binding domain of p73, resulting in the activation of p21 or Bax transcription, a downstream target of p73. Overexpression of ATF3 prolonged the half-life of TAp73beta by inhibiting its ubiquitination and thereby enhancing its transactivation and proapoptotic activities. Additionally, ATF3 induced by paclitaxel potentiated the stability of TAp73beta, not its transcriptional level. Chromatin immunoprecipitation analyses show that TAp73beta and ATF3 are recruited directly to the p21 and Bax promoter. Collectively, these results reveal that overexpression of ATF3 potentiates paclitaxel-induced apoptosis of HeLa cells, at least in part, by enhancing TAp73beta's stability and its transcriptional activity. The investigation shows that ATF3 may function as a tumor-inhibiting factor through direct regulatory effects on TAp73beta, suggesting a functional link between ATF3 and TAp73beta.
authors.affiliation: Center for Biomedical Sciences, NIH, Seoul 122-701, Korea.
authors.forename: Yeo Kyoung
authors.initials: YK
authors.lastname: Oh
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Mi-Hee
authors.initials: MH
authors.lastname: Jeong
authors.forename: Marie
authors.initials: M
authors.lastname: Rhee
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Mo
authors.forename: Eun Hyeon
authors.initials: EH
authors.lastname: Song
authors.forename: Joong-Yeon
authors.initials: JY
authors.lastname: Lim
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Choi
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.forename: Sang Ick
authors.initials: SI
authors.lastname: Park
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Yongil
authors.initials: Y
authors.lastname: Kwon
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kim
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013816:Thermodynamics; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D051700:Activating Transcription Factor 3; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D017239:Paclitaxel