Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.27 (
AMPK
)
6,299
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cadmium (Cd) is a toxic metal that is widely found in numerous environmental matrices and induces serious adverse effects in various organs and tissues. Bone tissue seems to be a crucial target of Cd contamination. Macroautophagy/autophagy has been proposed to play a pivotal role in Cd-mediated bone toxicity. However, the mechanisms that underlie Cd-induced autophagy are not yet completely understood. We demonstrated that Cd treatment increased autophagic flux and inhibition of the autophagic process using Atg7 gene silencing blocked the Cd-induced mesenchymal stem cell death. Mechanistically, Cd activated nuclear translocation of TFE3 but not that of TFEB or MITF, which contributed to the expression of autophagy-related genes and lysosomal biogenesis. Specifically, Cd decreased expression of phospho-AKT (Ser473). The reduction in AKT activity led to dephosphorylation of cytosolic TFE3 at Ser565 and promoted TFE3 nuclear translocation independently of MTORC1. Notably, Cd treatment increased the activity of PPP3/calcineurin, and pharmacological inhibition of PPP3/calcineurin with
FK506
suppressed AKT dephosphorylation and TFE3 activity. These results suggest that PPP3/calcineurin negatively regulates AKT phosphorylation and is involved in Cd-induced TFE3-dependent autophagy. Modulation of the PPP3/calcineurin-AKT-TFE3 autophagic-lysosomal machinery may offer novel therapeutic approaches for the treatment of Cd-induced bone damage. Abbreviations: ACTB: actin: beta; AKT: thymoma viral proto-oncogene;
AMPK
: AMP-activated protein kinase; ATG: autophagy related; Baf A1: bafilomycin A
1
; Cd: cadmium; FOXO3: forkhead box O3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MITF: melanogenesis associated transcription factor; MSC: mesenchymal stem sell; MTORC1: mechanistic target of rapamycin kinase complex 1; RPS6KB1: ribosomal protein S6 kinase: polypeptide 1; SGK1: serum/glucocorticoid regulated kinase 1; SQSTM1/p62: sequestosome 1;TFE3: transcription factor E3; TFEB: transcription factor EB; TFEC: transcription factor EC.
...
PMID:AKT inhibition-mediated dephosphorylation of TFE3 promotes overactive autophagy independent of MTORC1 in cadmium-exposed bone mesenchymal stem cells. 3032 47
It is usually accepted that prion proteins induce apoptosis in nerve cells. However, the mechanisms of PrP
Sc
-neurotoxicity are not completely clear. Calcineurin is a Ca
2+
/calmodulin-dependent phosphatase. It activates autophagy, and may represent a link between deregulation of Ca
2+
homeostasis and neuronal cell death. In this study, the effect of calcineurin activation mediated by human prion protein induced neuronal cell death via
AMPK
dephosphorylation and autophagy, was investigated. Synthetic peptides of PrP (PrP 106-126) increased calcineurin activity, without changing the levels of this protein phosphatase. Furthermore, these peptides reduced the levels of
AMPK
phosphorylation at threonine residue 172 and in autophagy activation. Calcineurin inhibitor,
FK506
, prevented this effect. The data showed that PrP-treated neurons had lower levels of
AMPK
than control neurons. This decrease in
AMPK
levels was matched via activation of autophagy.
FK506
prevented the changes in
AMPK
and autophagy levels induced by PrP peptides. Taken together, the data demonstrated that prion peptides triggered an apoptotic cascade via calcineurin activation, which mediated
AMPK
dephosphorylation and autophagy activation. Therefore, these data suggest that therapeutic strategies targeting calcineurin inhibition might facilitate the management of neurodegenerative disorders including prion disease.
...
PMID:Human prion protein-mediated calcineurin activation induces neuron cell death via AMPK and autophagy pathway. 3186 8
