Relationship between radiosensitivity and Nrf2 target gene expression in human hematopoietic stem cells.
NFE2-related factor 2 (Nrf2), which belongs to the cap "n" collar family of basic region leucine zipper transcription factors, is a key protein in the coordinated transcriptional induction of expression of various antioxidant genes. The purpose of this study was to analyze the expression of Nrf2 target genes, such as heme oxygenase 1 (HO-1), ferritin heavy polypeptide 1 (FTH1), NAD(P)H dehydrogenase, quinone 1 (NQO1), glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, glutathione reductase (GSR) and thioredoxin reductase 1 (TXNRD1), after X irradiation of CD34(+) cells that were prepared from human placental/umbilical cord blood hematopoietic stem cells (HSCs). We evaluated the relationship between radiosensitivity and expression of Nrf2 target genes in HSCs. The number of colony-forming cells derived from 2-Gy-irradiated HSCs decreased to approximately 20% of the nonirradiated control. At the same time, the mRNA expression of HO-1, FTH1, NQO1, GSR and TXNRD1 was significantly increased after X irradiation. A statistically significant negative correlation was observed between the surviving fraction of HSCs and the intrinsic NQO1 mRNA expression, indicating that HSCs in which NQO1 mRNA levels are low may also be radioresistant. The present results suggest that the antioxidant system associated with Nrf2 is involved in the radiosensitivity of HSCs.
Kato
Kengo
K
Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan.
Takahashi
Kenji
K
Monzen
Satoru
S
Yamamoto
Hiroyuki
H
Maruyama
Atsushi
A
Itoh
Ken
K
Kashiwakura
Ikuo
I
D001052:Apoferritins / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000528:radiation effects; D005980:Glutathione Reductase / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology* / Q000528:radiation effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000528:radiation effects; D009252:NADPH Dehydrogenase / Q000235:genetics / Q000528:radiation effects; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054481:Thioredoxin Reductase 1 / Q000235:genetics; D014965:X-Rays
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D001052:Apoferritins; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D009252:NADPH Dehydrogenase; D005980:Glutathione Reductase; D054481:Thioredoxin Reductase 1; D005721:Glutamate-Cysteine Ligase