The phosphoinositide 3-kinase pathway and glycogen synthase kinase-3 positively regulate the activity of metal-responsive transcription factor-1 in response to zinc ions

Abstract

Metal-responsive transcription factor-1 (MTF-1) is a metal-regulatory transcription factor essential for induction of the genes encoding metallothioneins (MTs) in response to transition metal ions. Activation of MTF-1 is dependent on the interaction of zinc with the zinc fingers of the protein. In addition, phosphorylation is essential for MTF-1 transactivation. We previously showed that inhibition of phosphoinositide 3-kinase (PI3K) abrogated Mt expression and metal-induced MTF-1 activation in human hepatocellular carcinoma (HCC) HepG2 and mouse L cells, thus showing that the PI3K signaling pathway positively regulates MTF-1 activity and Mt gene expression. However, it has also been reported that inhibition of PI3K has no significant effects on Mt expression in immortalized epithelial cells and increases Mt expression in HCC cells. To further characterize the role of the PI3K pathway on the activity of MTF-1, transfection experiments were performed in HEK293 and HepG2 cells in presence of glycogen synthase kinase-3 (GSK-3), mTOR-C1, and mTOR-C2 inhibitors, as well as of siRNAs targeting Phosphatase and TENsin homolog (PTEN). We showed that inhibition of the mTOR-C2 complex inhibits the activity of MTF-1 in HepG2 and HEK293 cells, while inhibition of the mTOR-C1 complex or of PTEN stimulates MTF-1 activity in HEK293 cells. These results confirm that the PI3K pathway positively regulates MTF-1 activity. Finally, we showed that GSK-3 is required for MTF-1 activation in response to zinc ions.

The classic metal‐sensing transcription factor MTF1 promotes myogenesis in response to copper

“…In this work, we found that in myoblasts differentiated in the absence of insulin, the expression of MTF1 was decreased. This evidence points to a potential regulation of MTF1 expression and phosphorylation mediated by PI3K, and possibly other kinases, in the skeletal muscle lineage, which is in agreement with previous studies (78). Whether the activation of these kinases is regulated by Cu or Zn in the skeletal muscle lineage remains to be elucidated.…”

“…MTF1 transcriptional activity is associated with the availability of Zn ions (73); however, the molecular mechanisms by which metals activate MTF1 remain unclear. Current models for MTF1 activation include: 1) stimulation by free cytosolic Zn; 2) interaction with Zn released from metallothioneins (MTs); or 3) MTF1 phosphorylation/dephosphorylation (72,(74)(75)(76)(77)(78). Under normal conditions, MTF1 is primarily located in the cytoplasm.…”

Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action of Huo-Xiang-Zheng-Qi Formula for the Treatment of Gastrointestinal Diseases

“…PI3K-Akt signaling pathway negatively modulates LPS-induced acute inflammatory responses. Factually, its inhibition enhances the activation of NF-κB, AP-1, and Egr-1 transcription factors as well as expression of TNF-α, IL-6 and tissue factor in human monocytic cells (Huang et al, 2011), which results in impaired immune responses and reduced susceptibility to autoimmune and inflammation (Andeol et al, 2018). This pathway is also involved in the regulation of autophagy in immune response, so as to remove bacteria from gastrointestinal infections.…”

The enhanced treatment efficacy of invasive brain glioma by dual-targeted artemether plus paclitaxel micelles

“…Matrix metalloproteinases (MMPs) is a group of endopeptidases that can degrade extracellular matrix protein in tumour microenvironment [37], thereby causing tumour cells to lose their connection to the basement membrane [38]. The PI3K/Akt/m TOR signalling pathway is a very important pathway in the cell signalling pathway [39,40]. PI3K signalling disorders are closely related to the occurrence and development of malignant tumours, and affect the formation of VM channels [41].…”