Related Experiment Videos
Molecular mechanisms of ionizing radiation-induced apoptosis
1Cancer Research Unit, Queensland Institute of Medical Research, Brisbane, Queensland, Australia. dianneW@qimr.edu.au
Abstract:
Ionizing radiation activates not only signalling pathways in the nucleus as a result of DNA damage, but also signalling pathways initiated at the level of the plasma membrane. Proteins involved in DNA damage recognition include poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, p53 and ataxia- telangiectasia mutated (ATM). Many of these proteins are inactivated by caspases during the execution phase of apoptosis. Signalling pathways outside the nucleus involve tyrosine kinases such as stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), protein kinase C, ceramide and reactive oxygen species. Recent evidence shows that tumour cells resistant to ionizing radiation-induced apoptosis have defective ceramide signalling. How these signalling pathways converge to activate the caspases is presently unknown, although in some cell types a role for calpain has been suggested.
Insights
Ionizing radiation triggers nuclear and plasma membrane signaling pathways. Defective ceramide signaling in tumor cells correlates with resistance to radiation-induced apoptosis, highlighting its critical role.
Area of Science:
- Cellular biology
- Molecular oncology
- Radiation biology
Background:
- Ionizing radiation (IR) induces DNA damage, activating nuclear signaling pathways involving proteins like PARP, DNA-PK, p53, and ATM.
- IR also activates extranuclear signaling cascades originating from the plasma membrane, including those involving tyrosine kinases, protein kinase C, ceramide, and reactive oxygen species.
Purpose of the Study:
- To elucidate the distinct and converging signaling pathways activated by ionizing radiation.
- To investigate the role of plasma membrane-initiated signaling, particularly ceramide pathways, in radiation-induced apoptosis and resistance.
Main Methods:
- Review of current literature on cellular responses to ionizing radiation.
- Analysis of signaling proteins involved in both nuclear (DNA damage response) and extranuclear pathways.
- Examination of evidence linking ceramide signaling defects to radioresistance in tumor cells.
Main Results:
- Nuclear signaling proteins (PARP, DNA-PK, p53, ATM) are activated by DNA damage but can be inactivated by caspases during apoptosis.
- Extranuclear signaling involves stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), protein kinase C, ceramide, and reactive oxygen species.
- Defective ceramide signaling is associated with tumor cell resistance to ionizing radiation-induced apoptosis.
Conclusions:
- Ionizing radiation activates complex signaling networks both inside and outside the nucleus.
- Ceramide signaling plays a crucial role in mediating apoptosis following radiation exposure, and its defects contribute to radioresistance.
- The precise mechanisms by which these pathways converge to activate caspases remain an area for further investigation, with calpain suggested in some contexts.