Recently, mitochondria have been suggested to act in tumor suppression. However, the underlying mechanisms by which mitochondria suppress tumorigenesis are far from being clear. In this study, we have investigated the link between mitochondrial dysfunction and the tumor suppressor protein p53 using a set of respiration-deficient (Res ؊ ) mammalian cell mutants with impaired assembly of the oxidative phosphorylation machinery. Our data suggest that normal mitochondrial function is required for ␥-irradiation (␥IR)-induced cell death, which is mainly a p53-dependent process. The Res ؊ cells are protected against ␥IR-induced cell death due to impaired p53 expression/ function. We find that the loss of complex I biogenesis in the absence of the MWFE subunit reduces the steady-state level of the p53 protein, although there is no effect on the p53 protein level in the absence of the ESSS subunit that is also essential for complex I assembly. The p53 protein level was also reduced to undetectable levels in Res ؊ cells with severely impaired mitochondrial protein synthesis. This suggests that p53 protein expression is differentially regulated depending upon the type of electron transport chain/respiratory chain deficiency. Moreover, irrespective of the differences in the p53 protein expression profile, ␥IR-induced p53 activity is compromised in all Res ؊ cells. Using two different conditional systems for complex I assembly, we also show that the effect of mitochondrial dysfunction on p53 expression/function is a reversible phenomenon. We believe that these findings will have major implications in the understanding of cancer development and therapy.Mitochondrial dysfunction is associated with aging, degenerative diseases, and cancer (1-3). One of the key functions of mitochondria is to make ATP by the process of oxidative phosphorylation (OxPhos), 2 which is carried out by four electron transport chain (ETC)/respiratory chain (RC) complexes (I-IV) and the ATP synthase (complex V). The OxPhos machinery consists of over 100 nuclear and mitochondrial DNA-encoded proteins (4). Thirteen proteins encoded by mitochondrial (mt) DNA are core proteins of complexes I and III-V that are synthesized inside mitochondria. Complex II is an exception as all of its subunits are encoded by nuclear genes. Mutations in both mtDNA and nuclear genes encoding OxPhos complexes are associated with almost all types of cancers (1, 3). Somatic mutations in complex I subunit-encoding genes are frequently associated with oncocytomas (5, 6). A recent study with head and neck cancers suggests that there are no mutational hot spots in the mtDNA (7). However, other studies suggest that mtDNA polymorphisms may predispose certain populations to cancer (8 -12). The association of germ line mutations in complex II subunits with hereditary paragangliomas and pheochromocytomas constitute the strongest evidence for implicating mitochondrial metabolism in tumorigenesis (13,14). Furthermore, the association of reduced expression of several subunits of OxPhos comple...
BackgroundThe Deepwater Horizon disaster was the largest marine oil spill in history, and total vertical exposure of oil to the water column suggests it could impact an enormous diversity of ecosystems. The most vulnerable organisms are those encountering these pollutants during their early life stages. Water-soluble components of crude oil and specific polycyclic aromatic hydrocarbons have been shown to cause defects in cardiovascular and craniofacial development in a variety of teleost species, but the developmental origins of these defects have yet to be determined. We have adopted zebrafish, Danio rerio, as a model to test whether water accumulated fractions (WAF) of the Deepwater Horizon oil could impact specific embryonic developmental processes. While not a native species to the Gulf waters, the developmental biology of zebrafish has been well characterized and makes it a powerful model system to reveal the cellular and molecular mechanisms behind Macondo crude toxicity.ResultsWAF of Macondo crude oil sampled during the oil spill was used to treat zebrafish throughout embryonic and larval development. Our results indicate that the Macondo crude oil causes a variety of significant defects in zebrafish embryogenesis, but these defects have specific developmental origins. WAF treatments caused defects in craniofacial development and circulatory function similar to previous reports, but we extend these results to show they are likely derived from an earlier defect in neural crest cell development. Moreover, we demonstrate that exposure to WAFs causes a variety of novel deformations in specific developmental processes, including programmed cell death, locomotor behavior, sensory and motor axon pathfinding, somitogenesis and muscle patterning. Interestingly, the severity of cell death and muscle phenotypes decreased over several months of repeated analysis, which was correlated with a rapid drop-off in the aromatic and alkane hydrocarbon components of the oil.ConclusionsWhether these teratogenic effects are unique to the oil from the Deepwater Horizon oil spill or generalizable for most crude oil types remains to be determined. This work establishes a model for further investigation into the molecular mechanisms behind crude oil mediated deformations. In addition, due to the high conservation of genetic and cellular processes between zebrafish and other vertebrates, our work also provides a platform for more focused assessment of the impact that the Deepwater Horizon oil spill has had on the early life stages of native fish species in the Gulf of Mexico and the Atlantic Ocean.
Prenylated Rab acceptor domain family member 1 (PRAF1), a transmembrane protein whose precise function is unknown, localizes to the Golgi complex, post-Golgi vesicles, lipid rafts, endosomes, and the plasma membrane. VAMP2 and Rab3A are SNARE proteins that interact with PRAF1, and, as part of a SNARE complex, PRAF1 may function in the regulation of docking and fusion of transport vesicles both in the Golgi complex and at the plasma membrane. Alternately, PRAF1 may function as a sorting protein in the Golgi complex. In addition to interacting with SNARE proteins, PRAF1 interacts with rotaviral, retroviral, and herpes viral proteins. The function of viral protein interaction is unknown, but PRAF1 may enhance rotaviral and retroviral assembly. In contrast, PRAF1 may inhibit the herpes virus life cycle.
Breast cancer is the most common tumor among women with inherited variants in the TP53 tumor suppressor, but onset varies widely suggesting interactions with genetic or environmental factors. Rodent models haploinsufficent for Trp53 also develop a wide variety of malignancies associated with Li-Fraumeni Syndrome, but BALB/c mice are uniquely susceptible to mammary tumors and is genetically linked to the Suprmam1 locus on chromosome 7. To define mechanisms that interact with deficiencies in p53 to alter susceptibility to mammary tumors, we fine-mapped the Suprmam1 locus in females from an N2 backcross of BALB/cMed and C57BL/6J mice. A major modifier was localized within a 10 cM interval on chromosome 7. The effect of the locus on DNA damage responses was examined in the parental strains and mice that are congenic for C57BL/6J alleles on the BALB/cMed background (SM1- Trp53 +/− ). The mammary epithelium of C57BL/6J- Trp53 +/− females exhibited little radiation-induced apoptosis compared to BALB/cMed- Trp53 +/− and SM1- Trp53 +/− females indicating that the Suprmam1 B6/B6 alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1 B6/B6 alleles in SM1- Trp53 +/− mice were sufficient to confer the C57BL/6J- Trp53 +/− phenotypes in homology-directed repair and replication fork progression. The Suprmam1 B6/B6 alleles in SM1- Trp53 +/− mice appear to act in trans to regulate a panel of DNA repair and replication genes which lie outside the locus. Significance: Genetic variation in replication-associated DNA repair can modify consequences of heterozygous mutations in Trp53 and contribute to susceptibility to mammary tumors in mouse models of Li-Fraumeni syndrome.
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