Related Experiment Videos
Early response gene induction following DNA damage in astrocytoma cell lines
1Division of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 20115-6084.
Abstract:
Early response genes (ERGs) are a group of genes with low or absent expression in quiescent cells that can be induced rapidly by a variety of proliferation and differentiation stimuli. c-jun and c-fos are prototypes for this group of genes. Recent evidence suggests that DNA damaging agents such as cytotoxic drugs and ionizing radiation can elicit strong ERG induction, suggesting that these genes may be involved in DNA damage repair and/or cell death. Paralleling this interest in drug-induced ERG expression is a growing body of evidence implicating ERG expression as important to the intrinsic function of the central nervous system. We therefore set out to explore the pattern of chemotherapeutic drug- and radiation-induced c-jun and c-fos expression in neuroectodermally (astrocytic) derived cell lines. We have demonstrated that various chemotherapeutic agents and ionizing radiation can induce c-jun in a time- and concentration-dependent manner. Furthermore, this induction can be prevented by pretreatment of the cells with agents that protect against DNA damage. Finally, we have demonstrated that c-fos and c-jun expression and induction are discoordinately regulated, reflecting a difference in astrocytic cell lines compared to hematopoietic cell lines. The possible relevance of these observations to the clinical resistance of astrocytic tumors to standard chemotherapy and radiation is discussed.
Insights
Chemotherapy and radiation induce early response genes (ERGs) like c-jun in brain cells. This response, unlike in other cells, may explain why brain tumors resist treatment.
Area of Science:
- Molecular Biology
- Neuroscience
- Oncology
Background:
- Early response genes (ERGs) rapidly activate with stimuli like proliferation and differentiation.
- DNA damaging agents (chemotherapy, radiation) induce ERGs, suggesting roles in DNA repair or cell death.
- ERG expression is crucial for central nervous system function.
Purpose of the Study:
- Investigate c-jun and c-fos expression in response to chemotherapy and radiation in astrocytic (brain-derived) cell lines.
- Determine if ERG induction in these cells is protective against DNA damage.
- Compare ERG regulation in astrocytic versus hematopoietic cell lines.
Main Methods:
- Exposing astrocytic cell lines to various chemotherapeutic agents and ionizing radiation.
- Measuring c-jun and c-fos expression levels over time and at different drug concentrations.
- Assessing the effect of DNA-protective agents on ERG induction.
- Comparing ERG regulation patterns between astrocytic and hematopoietic cell lines.
Main Results:
- Chemotherapy and ionizing radiation induce c-jun in astrocytic cells in a time- and concentration-dependent manner.
- DNA-protective agents prevent this chemotherapy- and radiation-induced c-jun expression.
- c-fos and c-jun are regulated differently (discoordinately) in astrocytic cells compared to hematopoietic cells.
Conclusions:
- Chemotherapy and radiation induce c-jun in brain-derived cells, a process that can be blocked by DNA damage protection.
- Discoordinately regulated c-jun and c-fos expression in astrocytic cells may contribute to clinical resistance observed in brain tumors treated with chemotherapy and radiation.