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Apoptosis: live or die--hard work either way!
B W Gallaher1, R Hille, K Raile
1Children's Hospital, University of Leipzig, Oststrasse 21-25, 04317 Leipzig, Germany. kiw@server3.medizin.uni-leipzig.de
Abstract:
This review presents a brief overview of the cell's apoptotic machinery, including specific and indirect death signals. Specific death signals are transferred via death ligands, death receptors, and their intracellular signalling pathways. Indirect death signals cumulate a wide range of stimuli that potentially harm survival of cells. These include intercalating drugs, irradiation or altered intracellular signalling. Herein, a focal point is the mitochondrial control of specific death enzymes--so called caspases--by members of the pro-apoptotic Bax and BH3 subfamily or the anti-apoptotic Bcl-2 subfamily. While the initiation of cell death happens through a variety of signalling systems, the activation of caspases plays a pivotal role in the progression towards the final morphologic findings in cells undergoing apoptosis. Caspases appear to directly cleave and inactivate substrates that are clinical for the maintenance of cell structure and function but also regulate the activity of other enzymes that induce the apoptotic phenotype within the cell. The insulin-like growth factors (IGFs) are potent proliferation factors and potently inhibit apoptosis acting via the ubiquitously expressed IGF-I receptor. Within IGF-I receptor signalling, key to the inhibition of apoptosis are the RAS/RAF/mitogen-activated protein (MAP)-kinase pathway and the PI 3'-kinase pathway. To give an example of high clinical relevance of apoptosis within endocrine disorders, apoptotic death of pancreatic beta cells in type 1 diabetes disease and the involvement of IGF-II in beta cell survival and beta cell function is discussed in detail. Finally, further understanding of signalling systems that are involved in proliferation or in apoptosis might provide novel tools to treat or even heal disorders like type I diabetes.
Insights
Apoptosis, or programmed cell death, is regulated by caspases and influenced by growth factors like insulin-like growth factors (IGFs). Understanding these pathways may offer new treatments for diseases such as type 1 diabetes.
Area of Science:
- Molecular Biology
- Cell Biology
- Endocrinology
Background:
- Apoptosis is a crucial cellular process involving specific and indirect death signals.
- Cell death signals are mediated by death ligands, receptors, and intracellular pathways.
- Mitochondrial regulation of caspases by Bcl-2 family proteins is central to apoptosis.
Purpose of the Study:
- To review the mechanisms of apoptosis, focusing on caspase activation and regulation.
- To explore the role of insulin-like growth factors (IGFs) in inhibiting apoptosis.
- To discuss the clinical relevance of apoptosis in endocrine disorders, exemplified by type 1 diabetes.
Main Methods:
- Review of existing literature on apoptotic pathways and signaling.
- Analysis of the mitochondrial control of caspases by Bcl-2 family members.
- Examination of IGF signaling pathways (RAS/RAF/MAP-kinase and PI 3'-kinase) in apoptosis inhibition.
Main Results:
- Caspase activation is pivotal in executing apoptosis, cleaving substrates essential for cell structure and function.
- Insulin-like growth factors (IGFs), acting via the IGF-I receptor, potently inhibit apoptosis.
- Apoptotic death of pancreatic beta cells in type 1 diabetes is linked to IGF-II's role in beta cell survival.
Conclusions:
- Caspase activation is a key executioner of apoptosis, regardless of the initial death signal.
- IGF signaling pathways are critical for suppressing apoptosis and promoting cell survival.
- Further research into proliferation and apoptosis signaling may yield novel therapeutic strategies for type 1 diabetes and other disorders.