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Arsenite-induced germline apoptosis through a MAPK-dependent, p53-independent pathway in Caenorhabditis elegans
Bei Pei1, Shunchang Wang, Xiaoyin Guo
1Key Laboratory of Ion Beam Bioengineering, Chinese Academy of Sciences, Hefei, Anhui 230031, People's Republic of China.
Abstract:
Many studies have shown that arsenite is a potent inducer of apoptosis both in cells and tissues. However, there is a lack of appropriate in vivo animal models to study the underlying mechanisms of arsenite-induced apoptosis. Caenorhabditis elegans is an excellent model organism for studying many biological processes. We showed previously that C. elegans could be used as an in vivo system to investigate the genotoxic effects of arsenite. In order to elucidate the underlying mechanisms of arsenite-induced apoptosis in vivo, in the present study, we used the mutated alleles of the C. elegans homologue of known mammalian genes that are involved in the regulation of apoptosis. Our results showed that the loss-of-function mutations of p53/ cep-1 and DNA damage response (DDR) genes hus-1, clk-2, and egl-1 exhibited significant increase in germline apoptosis under arsenite exposure, whereas arsenite-induced germline apoptosis was blocked in loss-of-function alleles of extracellular signal-regulated kinase (ERK) (lin-45 (ku51), mek-2 (n1989), and mpk-1 (ku1)), c-Jun N-terminal kinase (JNK) (jkk-1 (km2), mek-1 (ks54), jnk-1 (gk7), mkk-4 (ju91)), and p38 ( nsy-1 (ag3), sek-1 (ag1), and pmk-1 (km25)) MAPK cascades. These results suggest that arsenite-induced apoptosis occurs independently of p53/ cep-1 and the DNA damage response (DDR) genes hus-1, clk-2, and egl-1 and that the C. elegans caspase gene ced-3, Apaf-1 homologue ced-4, and the MAPK signaling pathways are essential for germline apoptosis. Moreover, our study demonstrates that C. elegans could be a mammalian in vivo substitute model to study the mechanisms of apoptosis.
Insights
Arsenite exposure induces germline apoptosis in C. elegans independently of p53 and DNA damage response genes. MAPK signaling pathways are essential for this process, establishing C. elegans as a model for studying apoptosis.
Area of Science:
- Toxicology
- Cell Biology
- Developmental Biology
Background:
- Arsenite is a known inducer of apoptosis.
- There is a need for in vivo models to study arsenite-induced apoptosis mechanisms.
- Caenorhabditis elegans is a suitable model organism for biological studies.
Purpose of the Study:
- To elucidate the in vivo mechanisms of arsenite-induced apoptosis.
- To investigate the role of p53, DNA damage response (DDR) genes, and MAPK pathways in arsenite-induced apoptosis using C. elegans.
- To validate C. elegans as an in vivo model for studying apoptosis.
Main Methods:
- Utilized mutated alleles of C. elegans homologues for mammalian apoptosis-regulating genes.
- Examined germline apoptosis in C. elegans under arsenite exposure.
- Assessed the impact of loss-of-function mutations in p53/cep-1, DDR genes, and MAPK cascades (ERK, JNK, p38) on apoptosis.
Main Results:
- Loss-of-function mutations in p53/cep-1 and DDR genes (hus-1, clk-2, egl-1) increased germline apoptosis upon arsenite exposure.
- Arsenite-induced germline apoptosis was blocked in loss-of-function mutants of ERK, JNK, and p38 MAPK pathways.
- Caspase gene ced-3, Apaf-1 homologue ced-4, and MAPK pathways are essential for arsenite-induced germline apoptosis.
Conclusions:
- Arsenite-induced apoptosis in C. elegans is independent of p53/cep-1 and DDR genes.
- MAPK signaling pathways are crucial for arsenite-induced germline apoptosis.
- C. elegans serves as a valid in vivo model for studying mammalian apoptosis mechanisms.
