Cadmium-Induced Germline Apoptosis in Caenorhabditis elegans: The Roles of HUS1, p53, and MAPK Signaling Pathways

Abstract

The transition metal cadmium (Cd) has been shown to induce apoptosis in a variety of cell lines and tissues. Caspase activation of the tumor suppressor gene p53 and mitogen-activated protein kinase (MAPK) signaling cascades have been reported to be involved in Cd-induced apoptosis. However, the underlying pathways of Cd-induced apoptosis have not been clearly elucidated in the in vivo systems, primarily for the lack of appropriate animal models. The nematode Caenorhabditis elegans has been shown to be a good model to study basic biological processes, including apoptosis. In this study, we used the mutated alleles of C. elegans homologs of known mammalian genes that are involved in regulation of apoptosis. Sublethal doses of Cd exposure increased C. elegans germline apoptosis in a dose- and time-dependent manner. The loss-of-function mutations of DNA damage response (DDR) genes HUS1 and p53 exhibited significant increase in germline apoptosis under Cd exposure, and the depletion of p53 antagonist ABL1 significantly enhanced apoptosis. Cd-induced apoptosis was blocked in the loss-of-function alleles of both c-Jun N-terminal kinase (JNK) and p38 MAPK cascades, which behaved normally under gamma-irradiation. Our findings implicate that both JNK and p38 MAPK cascades participate in Cd-induced apoptosis. Together, the results of this study suggest the nonessential roles of the DDR genes hus1 and p53 in Cd-induced germline apoptosis and that the apoptosis occurs through the ASK1/2-MKK7-JNK and ASK1/2-MKK3/6-p38 signaling pathways in a caspase-dependent manner. Finally, our study demonstrates that C. elegans is a mammalian in vivo substitute model to study the mechanisms of Cd-induced apoptosis.

Genome-Wide Analyses of Metal Responsive Genes in Caenorhabditis elegans

“…However, Ni-induced germline apoptosis is decreased in mutant homologs of the JNK ( jkk-1 , mek-1 , jnk-1 , and mkk-4 loss-of-function strains) and p38 MAPK ( nsy-1 , sek-1 , pmk-1 , and pmk-3 loss-of-function strains) signaling cascades, indicating the significance of these two pathways in Ni-induced apoptosis in C. elegans (Kezhou et al, 2010). Similarly, Cd exposure in C. elegans also induces germline apoptosis in a manner dependent upon the JNK and p38 MAPK pathways, as indicated by the blockage of apoptosis in Cd-exposed JNK and p38 MAPK pathway homolog knockouts (except in loss-of-function pmk-3 mutants; Wang et al, 2008). Also analogous to Ni-induced apoptotic pathways, both cep-1 and hus-1 play non-essential roles in germline apoptosis in warms exposed to 50 μM Cd (Wang et al, 2008), suggesting the lack of involvement of the DNA damage response in mediating metal-induced apoptosis in C. elegans .…”

Regulation of Anoxic Death in Caenorhabditis elegans by Mammalian Apoptosis Signal-Regulating Kinase (ASK) Family Proteins

“…In 2002, Kim et al (2002) demonstrated that NSY-1 and its downstream MAPK kinase (MAP2K) SEK-1 and MAPK PMK-1 were indispensable for the immune response to various bacterial infections, including Pseudomonas aeruginosa. In addition, nsy-1 mutant animals have been reported to show sensitivity to gram-positive bacteria Staphylococcus aureus with a defect in germline apoptosis (Sifri et al 2003), sensitivity to oxidative stress (Kondo et al 2005), resistance to germline apoptosis upon arsenite or cadmium stimulation Wang et al 2008) and a defect in egg laying (Shivers et al 2009). These phenotypes of nsy-1 mutant animals strongly suggest that NSY-1 plays important roles in stress responses in C. elegans.…”

Heavy Metals Content in Paraphilometroides nemipteri from South China Sea may Influence Level of Glutathione and P38 Protein Expression

“…Blackwell et al (2015) showed that sodium arsenite or other oxidative stressors activated p38 kinase through phosphorylation process in C. elegans. On the other hand, a study by Wang et al (2008) reported that cadmium-induced germline apoptosis of C. elegans via JNK and p38 MAPK signalling pathways. Hence, we believed that arsenic and cadmium which are classified as metals without redox potential induced stress through p38 MAPK signalling pathways, but underlying stress pathways of P. nemipteri after the heavy metals exposure is not fully understood.…”