Biomedical subjects

Ciara A Ryan

Publications and source records attributed to Ciara A Ryan.

3 recordsLinked to original sources

PubMed2003

Caspases and neuronal development.

Recent developments have shown that inappropriate activation of apoptotic pathways contributes to many neurodegenerative diseases. The basic mechanisms that underlie apoptosis in neurodegenerative diseases are uncertain, although they likely represent the subversion of normal developmental programs. Several types of neuronal cell death have been reported, including autophagic and caspase-independent cell death. In this review we consider evidence for the participation of apoptotic caspases in neuronal development, and examine the hypothesis that differentiating neurons undergo stage-specific alterations in apoptosis sensitivity that may be due to caspase regulation. In addition, we present data supporting this hypothesis.

Caspases↗

PubMed2002

Inhibitor specificity of recombinant and endogenous caspase-9.

Apoptosis triggered through the intrinsic pathway by radiation and anti-neoplastic drugs is initiated by the activation of caspase-9. To elucidate control mechanisms in this pathway we used a range of synthetic and natural reagents. The inhibitory potency of acetyl-Asp-Glu-Val-Asp-aldehyde ('Ac-DEVD-CHO'), benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone ('Z-VAD-FMK') and the endogenous caspase inhibitor X-chromosome-linked inhibitor of apoptosis protein ('XIAP') against recombinant caspase-9 were predictive of the efficacy of these compounds in a cell-free system. However, the viral proteins CrmA and p35, although potent inhibitors of recombinant caspase-9, had almost no ability to block caspase-9 in this system. These findings were also mirrored in cell expression studies. We hypothesize that the viral inhibitors CrmA and p35 are excluded from reacting productively with the natural form of active caspase-9 in vivo, making the potency of inhibitors highly context-dependent. This is supported by survival data from a mouse model of apoptosis driven by Sindbis virus expressing either p35 or a catalytic mutant of caspase-9. These results consolidate previous findings that CrmA is a potent inhibitor of caspase-9 in vitro, yet fails to block caspase-9-mediated cell death.

Amino Acid Chloromethyl Ketones↗

PubMed2002

Reprieval from execution: the molecular basis of caspase inhibition.

The suppression of apoptosis is essential to the propagation of viruses, and to the control of development and homeostasis in insects and mammals. The central components of all apoptotic pathways are proteases of the caspase family. Therefore, it is not surprising that the processes of natural selection, as well as pharmaceutical chemists, have designed compounds that directly target caspase activity in attempts to regulate apoptosis. The mechanisms used by highly specialized naturally occurring caspase inhibitors (both host and viral) have remained obscure for some time. However, recently there has been significant progress in this field, particularly because of the structural elucidation of the complexes between caspases and an endogenous inhibitor (XIAP) and a viral inhibitor (p35). This article reviews the newly defined molecular basis for the regulation of the caspases by viral and endogenous inhibitors.

Apoptosis↗