Home  About us  Contact
 

Antiapoptotic Pathways (antiapoptotic + pathway)

Distribution by Scientific Domains
Medical Sciences80%

Selected Abstracts

Human ATP-dependent RNA/DNA helicase hSuv3p interacts with the cofactor of survivin HBXIP

FEBS JOURNAL, Issue 19 2005
Michal Minczuk
The human SUV3gene encodes an NTP-dependent DNA/RNA DExH box helicase predominantly localized in mitochondria. Its orthologue in yeast is a component of the mitochondrial degradosome complex involved in the mtRNA decay pathway. In contrast to this, the physiological function of human SUV3 remains to be elucidated. In this report we demonstrate that the hSuv3 protein interacts with HBXIP, previously identified as a cofactor of survivin in suppression of apoptosis and as a protein that binds the HBx protein encoded by the hepatitis B virus. Using deletion analysis we identified the region within the hSuv3 protein, which is responsible for binding to HBXIP. The HBXIP binding domain was found to be important for mitochondrial import and stability of the Suv3 protein in vivo. We discuss the possible involvement of the hSuv3p,HBXIP interaction in the survivin-dependent antiapoptotic pathway. [source]

Inhibition of nuclear factor ,B and phosphatidylinositol 3-kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor , in mice

LIVER INTERNATIONAL, Issue 5 2003
Motoaki Imose
Abstract: Background/aims: Tumor necrosis factor (TNF)-, itself does not induce liver injury in normal mice or hepatocytes. Rather, this event, especially in vitro, is explained by the fact that the TNF-,/TNF receptor system not only triggers downstream signals leading to apoptosis but also induces an antiapoptotic pathway through the activation of nuclear factor (NF)-,B. The aim of this study was to determine whether inhibition of antiapoptotic pathways influences the susceptibility of mice to TNF-,. Here, we focused on the roles of NF-,B and phosphatidylinositol 3-kinase (PI3K)-regulated serine/threonine kinase Akt. Methods: TNF-, was administered to BALB/c mice after treatment with an adenovirus expressing a mutant form I,B, (Ad5I,B), the PI3K inhibitor wortmannin, or both. Liver injury was assessed biochemically and histologically. The expression of Bcl-2 family members and caspase activity were examined. Results: In the mice livers, treatment with Ad5I,B or the wortmannin suppressed the activation of NF-,B or Akt, respectively. Suppression of either NF-,B or Akt showed a slight increase in transaminase levels and focal liver cell death after TNF-, administration. However, in mice treated with both Ad5I,B and wortmannin, TNF-, administration resulted in massive hepatocyte apoptosis and hemorrhagic liver destruction in mice. The combination of Ad5I,B, wortmannin, and TNF-, markedly increased the activation of caspase-3 and -9, and activated caspase-8 to a lesser degree, suggesting that TNF-,-induced hepatocyte apoptosis is dependent on type II cell death signaling pathway, probably through the mitochondria. Inhibition of the NF-,B and PI3K/Akt pathways had no effect on expression of Bcl-2 families. Conclusion: The inducible activation of NF-,B and constitutive activation of Akt regulate hepatocyte survival against TNF-,, which occurs independent of Bcl-2 families. [source]

Mechanisms by which inflammation may increase intestinal cancer risk in inflammatory bowel disease

INFLAMMATORY BOWEL DISEASES, Issue 8 2010
Pamela M. O'Connor PhD
Abstract Patients with ulcerative colitis and Crohn's disease are at increased risk of developing intestinal cancers via mechanisms that remain incompletely understood. However, chronic inflammation and repeated events of inflammatory relapse in inflammatory bowel disease (IBD) expose these patients to a number of signals known to have tumorigenic effects including persistent activation of the nuclear factor-,B and cyclooxygenase-2/prostaglandin pathways, release of proinflammatory mediators such as tumor necrosis factor-, and interleukin-6, and enhanced local levels of reactive oxygen and nitrogen species. These inflammatory signals can contribute to carcinogenesis via 3 major processes: 1) by increasing oxidative stress, which promotes DNA mutagenesis thus contributing to tumor initiation; 2) by activating prosurvival and antiapoptotic pathways in epithelial cells, thereby contributing to tumor promotion; and 3) by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of tumor cells, thus supporting tumor progression and metastasis. The present review integrates clinical and basic research observations in an attempt to provide a comprehensive understanding of how inflammatory processes may contribute to intestinal cancer development in IBD patients. (Inflamm Bowel Dis 2010) [source]

Inhibition of nuclear factor ,B and phosphatidylinositol 3-kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor , in mice

LIVER INTERNATIONAL, Issue 5 2003
Motoaki Imose
Abstract: Background/aims: Tumor necrosis factor (TNF)-, itself does not induce liver injury in normal mice or hepatocytes. Rather, this event, especially in vitro, is explained by the fact that the TNF-,/TNF receptor system not only triggers downstream signals leading to apoptosis but also induces an antiapoptotic pathway through the activation of nuclear factor (NF)-,B. The aim of this study was to determine whether inhibition of antiapoptotic pathways influences the susceptibility of mice to TNF-,. Here, we focused on the roles of NF-,B and phosphatidylinositol 3-kinase (PI3K)-regulated serine/threonine kinase Akt. Methods: TNF-, was administered to BALB/c mice after treatment with an adenovirus expressing a mutant form I,B, (Ad5I,B), the PI3K inhibitor wortmannin, or both. Liver injury was assessed biochemically and histologically. The expression of Bcl-2 family members and caspase activity were examined. Results: In the mice livers, treatment with Ad5I,B or the wortmannin suppressed the activation of NF-,B or Akt, respectively. Suppression of either NF-,B or Akt showed a slight increase in transaminase levels and focal liver cell death after TNF-, administration. However, in mice treated with both Ad5I,B and wortmannin, TNF-, administration resulted in massive hepatocyte apoptosis and hemorrhagic liver destruction in mice. The combination of Ad5I,B, wortmannin, and TNF-, markedly increased the activation of caspase-3 and -9, and activated caspase-8 to a lesser degree, suggesting that TNF-,-induced hepatocyte apoptosis is dependent on type II cell death signaling pathway, probably through the mitochondria. Inhibition of the NF-,B and PI3K/Akt pathways had no effect on expression of Bcl-2 families. Conclusion: The inducible activation of NF-,B and constitutive activation of Akt regulate hepatocyte survival against TNF-,, which occurs independent of Bcl-2 families. [source]

Association of the TRAF1/C5 locus with increased mortality, particularly from malignancy or sepsis, in patients with rheumatoid arthritis

ARTHRITIS & RHEUMATISM, Issue 1 2009
Vasileios F. Panoulas
Objective Recent genome-wide association studies have identified TRAF1/C5 as a rheumatoid arthritis (RA) susceptibility locus. Tumor necrosis factor receptor,associated factor 1 (TRAF1) has been implicated in the regulation of antiapoptotic pathways, whereas C5 has a well-established role in defense against infection. The purpose of this study was to examine the association of the TRAF1/C5 locus with death in patients with RA. Methods Genomic DNA samples were collected from a prospective cohort of 400 RA patients. TRAF1/C5 rs3761847 was identified using real-time polymerase chain reaction and melting curve analyses. The association of TRAF1/C5 rs3761847 alleles with the risk of death was assessed using Cox proportional hazards regression analyses. Results TRAF1/C5 rs3761847 GG homozygote status was associated with an increased risk of death (hazard ratio 3.96 [95% confidence interval 1.24,12.6], P = 0.020) as compared with AA homozygote status. The excess mortality was attributed to deaths due to malignancies and sepsis but not cardiovascular disease (CVD). This polymorphism was one of the strongest predictors of death in RA (for TRAF1/C5 GG versus AA, hazard ratio 3.85 [95% confidence interval 1.18,12.59], P = 0.026) alongside the erythrocyte sedimentation rate, triglyceride level, prednisolone use, and age. Conclusion The risk of death in RA is increased in TRAF1/C5 rs3761847 GG homozygotes and appears to be independent of RA activity and severity as well as comorbidities relevant to CVD. If this finding is replicated in future studies, TRAF1/C5 genotyping could identify patients at increased risk of death, particularly death due to malignancy or sepsis. [source]