Type

Journal Article

Authors

Noel G McElvaney
Shane J O'Neill
Clifford C Taggart
Matthew W Lawless
Caitriona McLean
Catherine M Greene
Stanley D W Miller

Subjects

Biochemistry

Topics
phosphatidylinositol 3 kinases secretion metabolism caspases initiator humans phosphorylation physiology pharmacology cytochromes c drug effects bad protein human caspase 3 alpha 1 antitrypsin bcl associated death protein antagonists inhibitors apoptosis cells cultured taurochenodeoxycholic acid casp4 protein human tauroursodeoxycholic acid

Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha-1 antitrypsin via inhibition of Bad. (2007)

Abstract Z alpha-1 antitrypsin (AAT) deficiency is a genetic disease associated with accumulation of misfolded AAT in the endoplasmic reticulum (ER) of hepatocytes. ZAAT-expressing cells display ER stress responses including nuclear factor kappaB activation and apoptosis. Using an in vitro model of ZAAT ER accumulation, we investigated the mechanism of ZAAT-mediated ER-induced apoptosis and evaluated methods to inhibit this process. Here we demonstrate that expression of ZAAT, but not normal MAAT, in HEK293 cells leads to cleavage and activation of caspase-4 and induces apoptosis that is characterized by activation of caspase-3 and caspase-7 and DNA fragmentation. Similar effects are also induced using the ER agonist thapsigargin. A caspase-4-specific short interfering RNA (siRNA) does not impair ZAAT-induced caspase-3/7 activation or cell death in these cells. However, inhibition studies performed using tauroursodeoxycholic acid (TUDCA) demonstrate its ability to inhibit caspase-4 and caspase-3/7 activation, mitochondrial cytochrome c release, and caspase-3 cleavage induced by ZAAT and to promote cell survival. The mechanism by which TUDCA (tauroursodeoxycholic acid) promotes cell survival in ZAAT-expressing cells involves phosphorylation and inactivation of the proapoptotic factor Bad. TUDCA is unable to rescue cells from apoptosis or phosphorylate Bad in the presence of LY294002, a selective P-I-3-kinase inhibitor. CONCLUSION: These data show that caspase-4 is not essential for ZAAT-induced apoptosis in HEK293 cells and implicates P-I-3-kinase and Bad as potential therapeutic targets for the liver disease associated with ZAAT deficiency.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Noel G McElvaney, Shane J O'Neill, Clifford C Taggart, Matthew W Lawless, Caitriona McLean, Catherine M Greene, Stanley D W Miller

Experts in our system

1
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194
 
2
Shane J O'Neill
Royal College of Surgeons in Ireland
Total Publications: 84
 
3
Clifford C Taggart
Royal College of Surgeons in Ireland
Total Publications: 54
 
4
Catherine M Greene
Royal College of Surgeons in Ireland
Total Publications: 150