Activation of mammalian Tolloid-like 1 expression by hypoxia in human neuroblastoma SH-SY5Y cells.
Mammalian Tolloid-like 1 (mTll-1) is an astacin metalloprotease that is a member of the Tolloid family of proteins. mTll-1 cleaves chordin, an inhibitor of bone morphogenetic proteins (BMPs) and potentiates activity of the BMPs. Prenatal stress and glucocorticoids decrease mTll-1 expression whereas voluntary exercise increase mTll-1 gene expression in the mouse hippocampus. Here, we studied the underlying molecular mechanisms by which hypoxia regulates human mTll-1 gene expression. When cells were subjected to hypoxia, the expression of endogenous mTll-1 was upregulated in SH-SY5Y human neuroblastoma cells. Dual-luciferase assay and site-directed mutagenesis showed the presence of hypoxia responsive elements (HREs) at position 625 that was essential for activation of mTll-1 expression under hypoxic conditions. The binding of hypoxia-inducible factor (HIF-1) protein to the HREs was confirmed by gel shift assay. These results indicate that the HRE motif is directly involved in the activation of the mTll-1 transcription under hypoxic conditions.
Sabirzhanova
Inna B
IB
Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, Vermillion, SD 57069, USA. isabirzh@usd.edu
Sabirzhanov
Boris E
BE
Keifer
Joyce
J
Clark
Timothy G
TG
D000818:Animals; D001665:Binding Sites; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051379:Mice; D050436:Regulatory Elements, Transcriptional; D055394:Tolloid-Like Metalloproteinases / Q000235:genetics*; D015854:Up-Regulation
D051793:Hypoxia-Inducible Factor 1; D055394:Tolloid-Like Metalloproteinases; C484478:TLL1 protein, human