Implication of Nrf2 and ATF4 in differential induction of CHOP by proteasome inhibition in thyroid cancer cells.
Proteasome inhibition may cause endoplasmic reticulum (ER) stress, which has been reported to be implicated in the antitumoral effects of proteasome inhibitors. CCAAT/enhancer-binding protein homologous protein (CHOP) is induced by a variety of adverse physiological conditions including ER stress and is involved in apoptosis. We have reported that distinct induction of CHOP contributes to the responsiveness of thyroid cancer cells to proteasome inhibitors. However, the mechanism underlying differential induction of CHOP by proteasome inhibitors in thyroid cancer cells has not been well characterized. In the current study, we characterized that proteasome inhibition primarily activated the amino acid response element 1 (AARE1) on the CHOP promoter. We also demonstrated that although proteasome inhibition caused similar accumulation of activating transcription factor 4 (ATF4) in a panel of thyroid cancer cells, distinct amounts of ATF4 were recruited to the AARE1 element of CHOP promoter. In addition, we demonstrated that NF-E2-related factor 2 (Nrf2) was also implicated in the induction of CHOP by precluding the binding of ATF4 to the CHOP promoter. This study highlights the molecular mechanisms by which ATF4 and Nrf2 can control CHOP induction in thyroid cancer cells by proteasome inhibition.
Department of Biochemistry & Molecular Biology, China Medical University, Shenyang, China.
Zhi-Hong
ZH
Zong
Zhen-Xian
ZX
Du
Ning
N
Li
Chao
C
Li
Qiang
Q
Zhang
Bao-Qin
BQ
Liu
Yifu
Y
Guan
Hua-Qin
HQ
Wang
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D020218:Response Elements; D013964:Thyroid Neoplasms; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
C497109:ATF4 protein, human; C497249:DDIT3 protein, human; D007976:Leupeptins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D061988:Proteasome Inhibitors; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D049410:Luciferases, Renilla; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde