Role of activating transcription factor 3 on TAp73 stability and apoptosis in paclitaxel-treated cervical cancer cells

Kyoung Oh Yeo, Jung Lee Hyun, Mi Hee Jeong, Marie Rhee, Ji Won Mo, Hyeon Song Eun, Joong Yeon Lim, Kyung Hee Choi, Inho Jo, Ick Park Sang, Bin Gao, Yongil Kwon, Won Ho Kim

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 TAp73β small interfering RNA (siRNA). In wild-type activating transcription factor 3 (ATF3)-overexpressed cells, paclitaxel enhanced apoptosis through increased α and β isoform expression of TAp73; however, these events were attenuated in cells containing inactive COOH-terminal-deleted ATF3 [ATF3(ΔC)] or ATF3 siRNA. In contrast, paclitaxel-induced ATF3 expression did not change in TAp73β-overexpressed or TAp73β siRNA-cotransfected cells. Furthermore, paclitaxel-induced ATF3 translocated into the nucleus where TAp73β is expressed, but not in ATF3(ΔC) or TAp73β 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 TAp73β by inhibiting its ubiquitination and thereby enhancing its transactivation and proapoptotic activities. Additionally, ATF3 induced by paclitaxel potentiated the stability of TAp73β, not its transcriptional level. Chromatin immunoprecipitation analyses show that TAp73β 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 TAp73β's stability and its transcriptional activity. The investigation shows that ATF3 may function as a tumor-inhibiting factor through direct regulatory effects on TAp73β, suggesting a functional link between ATF3 and TAp73β.

Original languageEnglish
Pages (from-to)1232-1249
Number of pages18
JournalMolecular Cancer Research
Volume6
Issue number7
DOIs
StatePublished - 1 Jul 2008

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