Cell signaling relies extensively on dynamic pools of redox-inactive metal ions such as sodium, potassium, calcium, and zinc, but their redox-active transition metal counterparts such as copper and iron have been studied primarily as static enzyme cofactors. Here we report that copper is an endogenous regulator of lipolysis, the breakdown of fat, which is an essential process in maintaining the body's weight and energy stores. Utilizing a murine model of genetic copper misregulation, in combination with pharmacological alterations in copper status and imaging studies in a 3T3-L1 white adipocyte model, we demonstrate that copper regulates lipolysis at the level of the second messenger, cyclic AMP (cAMP), by altering the activity of the cAMP-degrading phosphodiesterase PDE3B. Biochemical studies of the copper-PDE3B interaction establish copper-dependent inhibition of enzyme activity and identify a key conserved cysteine residue within a PDE3-specific loop that is essential for the observed copper-dependent lipolytic phenotype.
HIV-1 is a master at deceiving the immune system, usurping host biosynthetic machinery. Although HIV-1 is coated with host-derived glycoproteins only glycosylation of viral gp120 has been described. Herein we utilize lectin microarray technology to analyze the glycome of intact HIV-1 virions. We show that the glycan coat of human T-cell line-derived HIV-1 matches that of native immunomodulatory microvesicles. The carbohydrate composition of both virus and microvesicles is cell-line dependent, suggesting a mechanism to rapidly camouflage the virus within the host. In addition, binding of both virus and microvesicles to antiviral lectins is enriched over the host cell, raising concern about targeting these glycans for therapeutics. This work also sheds light on the binding of HIV-1 to galectin-1, an important human immune lectin. Overall, our work strongly supports the theory that HIV-1 co-opts the exocytic pathway of microvesicles, potentially explaining why eliciting a protective antiviral immune response is difficult.
Introduction The metastatic progression of cancer is a direct result of the disregulation of numerous cellular signaling pathways, including those associated with adhesion, migration, and invasion. Members of the Rac family of small GTPases are known to act as regulators of actin cytoskeletal structures and strongly influence the cellular processes of integrin-mediated adhesion and migration. Even though hyperactivated Rac proteins have been shown to influence metastatic processes, these proteins have never been directly linked to metastatic progression.
Carbohydrates encode biological information necessary for cellular function. The structural diversity and complexity of these sugar residues have necessitated the creation of novel methodologies for their study. This review highlights recent technological advancements that are starting to unravel the intricate web of carbohydrate biology. New methods for the analysis of both glycoconjugates and glycan structures are discussed. With the use of these innovative tools, the field of glycobiology is poised to take center-stage in the post-genomic era of modern biology and medicine. Glycomics or the systems-level study of carbohydrates (glycans) has emerged as an important area of research in the post-genomic era. Although proteins are tagged with a variety of post-translational modifications including phosphorylation, acetylation, and methylation, glycosylation is the most prevalent modification, occurring on at least 50% of all proteins (1). The vast majority of glycoproteins and glycolipids are found at the cell membrane creating a carbohydrate-coated surface which communicates with the extracellular world. Interactions with cell surface oligosaccharides play a critical role in numerous biological events including differentiation, cellular adhesion, immune responses, and host-pathogen interactions (2-7). For example, the expression of an α-2,6-sialyltransferase (ST6GALNAC5) has been shown to mediate metastasis of breast cancer cells to the brain by enhancing adhesion of tumor cells to brain tissue (8). Although there is increasing evidence for critical biological roles of carbohydrates, the challenges posed by the diversity of glycans have slowed progress in understanding this class of biopolymers. This review delineates the challenge of glycomics and how it is being met by the advent of new technologies to analyze both structural and functional aspects of carbohydrates.
Estrogen and structurally related molecules play critical roles in breast cancer. We reported that resveratrol (50 microM), an estrogen-like phytosterol from grapes, acts in an antiestrogenic manner in breast cancer cells to reduce cell migration and to induce a global and sustained extension of actin structures called filopodia. Herein, we report that resveratrol-induced filopodia formation is time-dependent and concentration-dependent. In contrast to resveratrol at 50 microM, resveratrol at 5 microM acts in a manner similar to estrogen by increasing lamellipodia, as well as cell migration and invasion. Because Rho GTPases regulate the extension of actin structures, we investigated a role for Rac and Cdc42 in estrogen and resveratrol signaling. Our results demonstrate that 50 microM resveratrol decreases Rac and Cdc42 activity, whereas estrogen and 5 microM resveratrol increase Rac activity in breast cancer cells. MDA-MB-231 cells expressing dominant-negative Cdc42 or dominant-negative Rac retain filopodia response to 50 microM resveratrol. Lamellipodia response to 5 microM resveratrol, estrogen, or epidermal growth factor is inhibited in cells expressing dominant-negative Rac, indicating that Rac regulates estrogen and resveratrol (5 microM) signaling to the actin cytoskeleton. These results indicate that signaling to the actin cytoskeleton by low and high concentrations of resveratrol may be differentially regulated by Rac and Cdc42.
Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we report here that this compound binds to copper to arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas.
Total sialic acid (TSA), lipid-associated sialic acid (LASA), and fucose were estimated in sera of 35 patients with precancerous lesion of the oral cavity, 68 patients with cancer of the oral cavity, and 25 age- and sex-matched non-chewers of both tobacco and betal nut and nonsmokers as controls. Significant elevation in the serum levels of TSA and LASA were observed in patients with the precancerous and cancer lesions when compared with the controls. Serum TSA levels were elevated significantly in patients with cancer when compared with those with precancerous lesions. Circulating TSA and LASA levels were found to reflect tumor burden and correlated well with stage of the disease. However, serum fucose levels did not show an increase corresponding to stage of the disease. The results suggests that combined evaluation of these markers may be useful in predicting early malignant change and also in assessing the spread and invasiveness of the disease in cancer of the oral cavity.
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