Role of unphosphorylated transcription factor STAT3 in late cerebral ischemia after subarachnoid hemorrhage

Molecular mechanisms behind increased cerebral vasospasm and local inflammation in late cerebral ischemia after subarachnoid hemorrhage (SAH) are poorly elucidated. Using system biology tools and experimental SAH models, we have identified signal transducer and activator of transcription 3 (STAT3) transcription factor as a possible major regulatory molecule. On the basis of the presence of transcription factor binding sequence in the promoters of differentially regulated genes (significant enrichment PE: 6 × 10(5)) and the consistent expression of STAT3 (mRNA, P=0.0159 and Protein, P=0.0467), we hypothesize that unphosphorylated STAT3 may directly DNA bind and probably affect the genes that are involved in inflammation and late cerebral ischemia to influence the pathologic progression of SAH.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 February 2014; doi:10.1038/jcbfm.2014.15

The FASEB Journal express article 10.1096/fj.02-0034fje. Published online August 7, 2002.

The role of caspases in cryoinjury: caspase inhibition strongly improves the recovery of cryopreserved hematopoietic and other cell

Review Viral Modulation of Cell Death by Inhibition of Caspases

Abstract. Caspases are key effectors of the apoptotic process. Some of them play important roles in the immune system, being involved in the proteolytic maturation of the key cytokines, including interleukin 1β (IL-1β) and IL-18. The latter directs the production of interferon γ (IFN-γ). Among pathogens, particularly viruses express various modulators of caspases that inhibit their activity by direct binding. By evading the apoptotic process, viruses can better control their production in the infected cell and avoid the attack of the immune system. Targeting the maturation of the key cytokines involved in the initiation of (antiviral) immune response helps to avoid recognition and eradication by the immune system. The three main classes of caspase inhibitors frequently found among viruses include serine proteinase inhibitors (serpins: CrmA/SPI-2), viral IAPs (vIAPs) and p35. Their molecular mechanisms of action, structures and overall influence on cellular physiology are discussed in the review below. Key words: CrmA; IAP; p35; caspase; granzyme B

Loss of Caspase-9 Reveals Its Essential Role for Caspase-2 Activation and Mitochondrial Membrane Depolarization

Caspase-9 plays an important role in apoptosis induced by genotoxic stress. Irradiation and anticancer drugs trigger mitochondrial outer membrane permeabilization, resulting in cytochrome c release and caspase-9 activation. Two highly contentious issues, however, remain: It is unclear whether the loss of the mitochondrial membrane potential ΔΨ(M) contributes to cytochrome c release and whether caspases are involved. Moreover, an unresolved question is whether caspase-2 functions as an initiator in genotoxic stress-induced apoptosis. In the present study, we have identified a mutant Jurkat T-cell line that is deficient in caspase-9 and resistant to apoptosis. Anticancer drugs, however, could activate proapoptotic Bcl-2 proteins and cytochrome c release, similarly as in caspase-9–proficient cells. Interestingly, despite these alterations, the cells retained ΔΨ(M). Furthermore, processing and enzyme activity of caspase-2 were not observed in the absence of caspase-9. Reconstitution of caspase-9 expression restored not only apoptosis but also the loss of ΔΨ(M) and caspase-2 activity. Thus, we provide genetic evidence that caspase-9 is indispensable for drug-induced apoptosis in cancer cells. Moreover, loss of ΔΨ(M) can be functionally separated from cytochrome c release. Caspase-9 is not only required for ΔΨ(M) loss but also for caspase-2 activation, suggesting that these two events are downstream of the apoptosome