Arsenite-induced germline apoptosis through a MAPK-dependent, p53-independent pathway in Caenorhabditis elegans.
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.
Pei
Bei
B
Key Laboratory of Ion Beam Bioengineering, Chinese Academy of Sciences, Hefei, Anhui 230031, People's Republic of China.
Wang
Shunchang
S
Guo
Xiaoyin
X
Wang
Jun
J
Yang
Gen
G
Hang
Haiying
H
Wu
Lijun
L
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000502:physiology; D004249:DNA Damage; D004195:Disease Models, Animal; D005854:Germ Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D013723:Teratogens / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D018053:Arsenites; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases; C015001:arsenite