Ionizing radiation-induced cancer: perplexities of the bystander effect.

Ionizing radiation (IR) is a carcinogen. This has been established beyond doubt from many years of studies such as those conducted among the survivors of the atomic bomb attacks on Hiroshima and Nagasaki and later from the Chernobyl accident. Despite immense progress in the field of carcinogenesis, complete understanding of the underlying mechanisms behind IR-induced cancer remains elusive.

Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype.

SUGCT (C7orf10) is a mitochondrial enzyme that synthesizes glutaryl-CoA from glutarate in tryptophan and lysine catabolism, but it has not been studied in vivo. Although mutations in Sugct lead to Glutaric Aciduria Type 3 disease in humans, patients remain largely asymptomatic despite high levels of glutarate in the urine. To study the disease mechanism, we generated SugctKO mice and uncovered imbalanced lipid and acylcarnitine metabolism in kidney in addition to changes in the gut microbiome.

Emi2 Is Essential for Mouse Spermatogenesis.

The meiotic functions of Emi2, an inhibitor of the APC/C complex, have been best characterized in oocytes where it mediates metaphase II arrest as a component of the cytostatic factor. We generated knockout mice to determine the in vivo functions of Emi2-in particular, its functions in the testis, where Emi2 is expressed at high levels. Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis but dispensable for embryonic development and mitotic cell divisions.

Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis.

Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model.

p27 is regulated independently of Skp2 in the absence of Cdk2.

Cyclin-dependent kinase 2 (Cdk2) is dispensable for mitotic cell cycle progression and Cdk2 knockout mice are viable due to the compensatory functions of other Cdks. In order to assess the role of Cdk2 under limiting conditions, we used Skp2 knockout mice that exhibit increased levels of Cdk inhibitor, p27(Kip1), which is able to inhibit Cdk2 and Cdk1. Knockdown of Cdk2 abrogated proliferation of Skp2(-/-) mouse embryonic fibroblasts, encouraging us to generate Cdk2(-/-)Skp2(-/-) double knockout mice.

Established and novel Cdk/cyclin complexes regulating the cell cycle and development.

The identification of new members in the Cdk and cyclin families, functions for many of which are still emerging, has added new facets to the cell cycle regulatory network. With roles extending beyond the classical regulation of cell cycle progression, these new players are involved in diverse processes such as transcription, neuronal function, and ion transport. Members closely related to Cdks and cyclins such as the Speedy/RINGO proteins offer fresh insights and hope for filling in the missing gaps in our understanding of cell division.

Regulation of peroxisome proliferator-activated receptors by e6-associated protein.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors (NRs) that regulate genes involved in lipid and glucose metabolism. PPAR activity is regulated by interactions with cofactors and of interest are cofactors with ubiquitin ligase activity. The E6-associated protein (E6-AP) is an E3 ubiquitin ligase that affects the activity of other NRs, although its effects on PPARs have not been examined.

Regulation of peroxisome proliferator-activated receptor-alpha by MDM2.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) belongs to the nuclear receptor (NR) family of transcription factors and regulates lipid and glucose metabolism. Like other NRs, the regulation of gene expression by PPARalpha depends on cofactor recruitment to the transcription complex and multiple protein-protein interactions. In this study, Murine Double Minute 2 (MDM2), an E3 ubiquitin ligase, is identified as a PPARalpha-interacting protein that regulates PPARalpha transcriptional activity.

Different mechanisms of vaccine-induced and infection-induced immunity to Bordetella bronchiseptica.

A recent resurgence in the number of cases of whooping cough, and other respiratory diseases caused by members of the bordetellae, in vaccinated populations has demonstrated the need for a thorough understanding of vaccine-induced immunity to facilitate more intelligent vaccine design. In this work, we use a murine model of respiratory infection using the highly successful animal pathogen, Bordetella bronchiseptica. Since previously infected animals have been shown to resist re-infection by B.

The ribosomal protein rpL11 associates with and inhibits the transcriptional activity of peroxisome proliferator-activated receptor-alpha.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor superfamily whose ligands, the peroxisome proliferators (PPs), are liver tumor promoters in rodents. Interaction cloning was performed using bacterially expressed PPARalpha to identify proteins involved in PP signaling. The ribosomal protein L11 (rpL11), a component of the large 60S subunit, was identified as a PPARalpha-associated protein.

Antibody-mediated bacterial clearance from the lower respiratory tract of mice requires complement component C3.

To assess the contribution of complement to respiratory immunity in the context of a natural bacterial infection, we used mice genetically deficient in complement components and the murine pathogen Bordetella bronchiseptica. Complement component C3 was not required for the control of bacterial infection or for the generation of infection-induced protective immunity. However, C3-deficient (C3(-/-)) mice were severely defective, compared to wild type, in vaccine-induced protective immunity.