TGF-β-activated kinase 1 promotes cell cycle arrest and cell survival of X-ray irradiated hela cells dependent on p21 induction but independent of NF-κB, p38 MAPK and ERK phosphorylations

Yukihiro Furusawa, Zheng Li Wei, Hiroaki Sakurai, Yoshiaki Tabuchi, Peng Li, Qing Li Zhao, Takaharu Nomura, Ikuo Saiki, Takashi Kondo

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Transforming growth factor-β-activated kinase 1 (TAK1) appears to play a role in inhibiting apoptotic death in response to multiple stresses. To assess the role of TAK1 in X-ray induced apoptosis and cell death, we irradiated parental and siRNA-TAK1-knockdown HeLa cells. Changes in gene expression levels with and without TAK1-knockdown were also examined after irradiation to elucidate the molecular mechanisms involved. After X-ray irradiation, cell death estimated by the colony formation assay increased in the TAK1-knockdown cells. Apoptosis induction, determined by caspase-3 cleavage, suggested that the increased radiosensitivity of the TAK1-knockdown cells could be partially explained by the induction of apoptosis. However, cell cycle analysis revealed that the percentage of irradiated cells in the G2/M-phase decreased, and those in the S-and SubG1-phases increased due to TAK1 depletion, suggesting that the loss of cell cycle checkpoint regulation may also be involved in the observed increased radiosensitivity. Interestingly, significant differences in the induction of NF-κB, p38 MAPK and ERK phosphorylation, the major downstream molecules of TAK1, were not observed in TAK1 knockdown cells compared to their parental control cells after irradiation. Instead, global gene expression analysis revealed differentially expressed genes after irradiation that bioinformatics analysis suggested are associated with cell cycle regulatory networks. In particular, CDKN1A (coding p21WAF1), which plays a central role in the identified network, was up-regulated in control cells but not in TAK1 knockdown cells after X-ray irradiation. Si-RNA knockdown of p21 decreased the percentage of cells in the G2/M phase and increased the percentage of cells in the S-and SubG1-phases after X-ray irradiation in a similar manner as TAK-1 knockdown. Taken together, these findings suggest that the role of TAK1 in cell death, cell cycle regulation and apoptosis after X irradiation is independent of NF-κB, p38 MAPK, and ERK phosphorylation, and dependent, in part, on p21 induction.

Original languageEnglish
Pages (from-to)766-774
Number of pages9
JournalRadiation Research
Volume177
Issue number6
DOIs
Publication statusPublished - 2012 Jun 1

ASJC Scopus subject areas

  • Biophysics
  • Radiation
  • Radiology Nuclear Medicine and imaging

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