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Polyploidization, the addition of a complete set of chromosomes to the genome, represents one of the most dramatic mutations known to occur. Nevertheless, polyploidy is well tolerated in many groups of eukaryotes. Indeed, the majority of flowering plants and vertebrates have descended from polyploid ancestors. This Review examines the short-term effects of polyploidization on cell size, body size,...
Duplicated genes escape gene loss by conferring a dosage benefit or evolving diverged functions. The yeast Saccharomyces cerevisiae contains many duplicated genes encoding ribosomal proteins. Prior studies have suggested that these duplicated proteins are functionally redundant and affect cellular processes in proportion to their expression. In contrast, through studies of ASH1 mRNA in yeast, we demonstrate...
Hypoxia, a condition of severe oxygen shortage, induces a transcriptional response that is important for both normal embryonic development and the growth of tumors. In this issue, Cheng et al. (2007) describe how the stability of the major transcriptional regulator of the hypoxic response, HIF1α, is modulated by the interplay between the ubiquitin and the SUMO conjugation systems.
SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1 −/− embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die...
In the budding yeast Saccharomyces cerevisiae, 59 of the 79 cytoplasmic ribosomal proteins are encoded by two genes, stemming from an ancient genome duplication event. Komili et al. (2007) now report that these paralogous genes are not functionally equivalent, suggesting the possible existence of a “ribosome code.”
Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca 2+ directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which...
Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of αPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. αPlGF inhibited growth and metastasis of various...
Cell entry of Simian Virus 40 (SV40) involves caveolar/lipid raft-mediated endocytosis, vesicular transport to the endoplasmic reticulum (ER), translocation into the cytosol, and import into the nucleus. We analyzed the effects of ER-associated processes and factors on infection and on isolated viruses and found that SV40 makes use of the thiol-disulfide oxidoreductases, ERp57 and PDI, as well as...
The unicellular parasite Trypanosoma brucei rapidly removes host-derived immunoglobulin (Ig) from its cell surface, which is dominated by a single type of glycosylphosphatidylinositol-anchored variant surface glycoprotein (VSG). We have determined the mechanism of antibody clearance and found that Ig-VSG immune complexes are passively sorted to the posterior cell pole, where they are endocytosed....
An agent that blocks tumor angiogenesis, growth, and metastasis without affecting normal tissues—whether used alone or in combination with currently approved drugs—would change the way we treat cancer. In this issue, Fischer et al. (2007) offer compelling evidence that a monoclonal antibody against placental growth factor (PlGF), a member of the VEGF family, has such potential in mice.
Last year marked the 25th anniversary of the recognition of what we now call AIDS. The AIDS pandemic has claimed more than 25 million lives, the majority of them in the developing world, and has exacerbated poverty and slowed human development. Although much has been accomplished in HIV/AIDS research, much remains to be done, especially regarding delivery of HIV/AIDS therapies and care and prevention...
In this issue, Pospisilik et al. (2007) demonstrate that a reduction in mitochondrial oxidative phosphorylation protects mice against obesity and diabetes. This finding suggests that the moderate deficiency in oxidative phosphorylation that is observed in peripheral tissues of insulin-resistant humans is not a causative factor in diabetes but may instead be a compensatory response.
Regulated intramembrane proteolysis is a method for transducing signals between cellular compartments. When protein folding is compromised in the periplasm of E. coli, the C termini of outer-membrane proteins (OMPs) bind to the PDZ domains of the trimeric DegS protease and activate cleavage of RseA, a transmembrane transcriptional regulator. We show here that DegS is an allosteric enzyme. OMP binding...
The recognition of specific DNA-binding sites by transcription factors is a critical yet poorly understood step in the control of gene expression. Members of the Hox family of transcription factors bind DNA by making nearly identical major groove contacts via the recognition helices of their homeodomains. In vivo specificity, however, often depends on extended and unstructured regions that link Hox...
Cell-to-cell variability in the timing of cell-fate changes can be advantageous for a population of single-celled organisms growing in a fluctuating environment. We study timing variability during meiosis in Saccharomyces cerevisiae, initiated upon nutritional starvation. We use time-lapse fluorescence microscopy to measure the timing of meiotic events in single cells and find that the duration of...
Type-2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Recent studies place altered mitochondrial oxidative phosphorylation (OxPhos) as an underlying genetic element of insulin resistance. However, the causative or compensatory nature of these OxPhos changes has yet to be proven. Here, we show that muscle- and liver-specific AIF ablation...
The liver stages of malaria are clinically silent but have a central role in the Plasmodium life cycle. Liver stages of the parasite containing thousands of merozoites grow inside hepatocytes for several days without triggering an inflammatory response. We show here that Plasmodium uses a PEXEL/VTS motif to introduce the circumsporozoite (CS) protein into the hepatocyte cytoplasm and a nuclear localization...
In Gram-negative bacteria, envelope stress signals such as unfolded outer membrane proteins (OMP) activate the periplasmic protease DegS. This protease then triggers a cellular pathway to alleviate the stress. Now Sohn et al. (2007) show conclusively that inhibition of DegS is relieved allosterically by binding of the C-terminal sequences in unfolded OMPs to the PDZ domain of DegS.
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