Hypoxia induces upregulation of the deoxyribonuclease I gene in the human pancreatic cancer cell line QGP-1.
We have previously demonstrated that ischemia caused by acute myocardial infarction induces an abrupt increase of serum deoxyribonuclease I (DNase I) activity. In this study, we examined whether hypoxia can affect the levels of DNase I activity and/or its transcripts in vitro. We first exposed the human pancreatic cancer cell line QGP-1, which is the first documented DNase-I-producing cell line, to hypoxia (2% O2), and found that this induced a significant increase in both the activity and transcripts of DNase I. This response was mediated by increased transcription only from exon 1a of the two alternative transcription-initiating exons utilized simultaneously in the human DNase I gene (DNASE1); exposure of QGP-1 cells to hypoxia for 24 h resulted in a 15-fold increase of DNASE1 transcripts starting from exon 1a compared with the expression level under normoxic conditions. Promoter, electrophoretic mobility shift, and chromatin immunoprecipitation assays with QGP-1 cells exposed to hypoxia or normoxia showed that the region just upstream from exon 1a was involved in this response in a hypoxia-induced factor-1-independent, but at least in a Sp1 transcription factor-dependent manner possibly through enhanced binding of Sp1 protein to the promoter. These results indicate that DNASE1 expression is upregulated by hypoxia in the cells.
Kominato
Yoshihiko
Y
Department of Legal Medicine and Medical Genetics, Gunma University, Graduate School of Medicine, Gunma, 371-8511, Japan.
Iida
Reiko
R
Nakajima
Tamiko
T
Tajima
Yutaka
Y
Takagi
Rie
R
Makita
Chikako
C
Kishi
Koichiro
K
Ueki
Misuzu
M
Kawai
Yasuyuki
Y
Yasuda
Toshihiro
T
D045744:Cell Line, Tumor; D003850:Deoxyribonuclease I / Q000096:biosynthesis* / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics*
D016329:Sp1 Transcription Factor; D003850:Deoxyribonuclease I