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Kowluru A.,Wayne State University | Kowluru A.,John ngell Va Medical Center
Endocrine Reviews | Year: 2010

Glucose-stimulated insulin secretion from the islet β-cell involves a sequence of metabolic events and an interplay between a wide range of signaling pathways leading to the generation of second messengers (e.g., cyclic nucleotides, adenine and guanine nucleotides, soluble lipid messengers) and mobilization of calcium ions. Consequent to the generation of necessary signals, the insulin-laden secretory granules are transported from distal sites to the plasma membrane for fusion and release of their cargo into the circulation. The secretory granule transport underlies precise changes in cytoskeletal architecture involving a well-coordinated cross-talk between various signaling proteins, including small molecular mass GTP-binding proteins (G proteins) and their respective effector proteins. The purpose of this article is to provide an overview of current understanding of the identity of small G proteins (e.g., Cdc42, Rac1, and ARF-6) and their corresponding regulatory factors (e.g., GDP/GTP-exchange factors, GDP-dissociation inhibitors) in the pancreatic β-cell. Plausible mechanisms underlying regulation of these signaling proteins by insulin secretagogues are also discussed. In addition to their positive modulatory roles, certain small G proteins also contribute to the metabolic dysfunction and demise of the islet β-cell seen in in vitro and in vivo models of impaired insulin secretion and diabetes. Emerging evidence also suggests significant insulin secretory abnormalities in small G protein knockout animals, further emphasizing vital roles for these proteins in normal healthandfunction of the islet β-cell. Potential significance of these experimental observations from multiple laboratories and possible avenues for future research in this area of islet research are highlighted. Copyright © 2010 by The Endocrine Society. Source

Horne S.D.,Wayne State University | Chowdhury S.K.,John ngell Va Medical Center | Heng H.H.Q.,Wayne State University
Frontiers in Genetics | Year: 2014

Cells are constantly exposed to various internal and external stresses. The importance of cellular stress and its implication to disease conditions have become popular research topics. Many ongoing investigations focus on the sources of stress, their specific molecular mechanisms and interactions, especially regarding their contributions to many common and complex diseases through defined molecular pathways. Numerous molecular mechanisms have been linked to endoplasmic reticulum stress along with many unexpected findings, drastically increasing the complexity of our molecular understanding and challenging how to apply individual mechanism-based knowledge in the clinic. A newly emergent genome theory searches for the synthesis of a general evolutionary mechanism that unifies different types of stress and functional relationships from a genome-defined system point of view. Herein, we discuss the evolutionary relationship between stress and somatic cell adaptation under physiological, pathological, and somatic cell survival conditions, the multiple meanings to achieve adaptation and its potential trade-off. In particular, we purposely defocus from specific stresses and mechanisms by redirecting attention toward studying underlying general mechanisms. © 2014 Horne, Chowdhury and Heng. Source

Kowluru A.,John ngell Va Medical Center | Kowluru A.,Wayne State University | Kowluru R.A.,Wayne State University
Biochemical Pharmacology | Year: 2015

Post-translational prenylation involves incorporation of 15-(farnesyl) or 20-(geranylgeranyl) carbon derivatives of mevalonic acid into highly conserved C-terminal cysteines of proteins. The farnesyl transferase (FTase) and the geranylgeranyl transferase (GGTase) mediate incorporation of farnesyl and geranylgeranyl groups, respectively. At least 300 proteins are prenylated in the human genome; the majority of these are implicated in cellular processes including growth, differentiation, cytoskeletal function and vesicle trafficking. From a functional standpoint, isoprenylation is requisite for targeting of modified proteins to relevant cellular compartments for regulation of effector proteins. Pharmacological and molecular biological studies have provided compelling evidence for key roles of this signaling pathway in physiological insulin secretion in normal rodent and human islets. Recent evidence indicates that inhibition of prenylation results in mislocalization of unprenylated proteins, and surprisingly, they remain in active (GTP-bound) conformation. Sustained activation of G proteins has been reported in mice lacking GGTase, suggesting alternate mechanisms for the activation of non-prenylated G proteins. These findings further raise an interesting question if mislocalized, non-prenylated and functionally active G proteins cause cellular pathology since aberrant protein prenylation has been implicated in the onset of cardiovascular disease and diabetes. Herein, we overview the existing evidence to implicate prenylation in islet function and potential defects in this signaling pathways in the diabetic β-cell. We will also identify critical knowledge gaps that need to be addressed for the development of therapeutics to halt defects in these signaling steps in β cells in models of impaired insulin secretion, metabolic stress and diabetes. © 2015 Published by Elsevier Inc. Source

Kowluru A.,John ngell Va Medical Center | Kowluru A.,Wayne State University | Kowluru R.A.,Wayne State University
Biochemical Pharmacology | Year: 2014

Increased intracellular generation of reactive oxygen species [ROS] has been implicated in the pathology of metabolic [diabetes] and neurodegenerative [Alzheimer's] diseases. Accumulating evidence suggests NADPH oxidases [Noxs] as the principal source for cellular ROS in humans. Of this class of enzymes, the phagocyte-like Nox [Nox2] has come under intense scrutiny as one of the "culprits" for the induction of cellular damage culminating in the onset of diabetes and its complications. Functional regulation of Nox2 is fairly complex due to its membranous [gp91phox, p22phox] and cytosolic [p40phox, p47phox, p67phox and Rac1] cores, which require specific post-translational modification steps [phosphorylation and lipidation] for their membrane association. Therefore, optimal efficacy of Nox2 depends upon precise regulation of these signaling steps followed by translocation of the cytosolic components to the membrane. Interestingly, numerous recent studies have reported sustained activation of Nox2, ROS-derived oxidative stress, and cellular dysfunction in in vitro and in vivo models of glucolipotoxicity and diabetes. These investigations employed a variety of cell-permeable peptides and pharmacological inhibitors to impede Nox2 holoenzyme assembly and activation in pancreatic islet β-cells, cardiomyocytes and retinal endothelial cells under conditions of glucolipotoxicity and diabetes. Herein, we highlight the existing evidence to implicate Nox2 as the "trigger" of cellular damage, and identify critical gaps in our current understanding that need to be addressed to further affirm the roles of Nox2 as a potential therapeutic target for the treatment of diabetes and other metabolic disorders. © 2014 Published by Elsevier Inc. Source

Funasaka T.,Nanzando Pharmacies Co. | Raz A.,Wayne State University | Nangia-Makker P.,Wayne State University | Nangia-Makker P.,John ngell Va Medical Center
Seminars in Cancer Biology | Year: 2014

Galectin-3, a member of β-galactoside-binding gene family is a multi-functional protein, which regulates pleiotropic biological functions such as cell growth, cell adhesion, cell-cell interactions, apoptosis, angiogenesis and mRNA processing. Its unique structure enables it to interact with a plethora of ligands in a carbohydrate dependent or independent manner. Galectin-3 is mainly a cytosolic protein, but can easily traverse the intracellular and plasma membranes to translocate into the nucleus, mitochondria or get externalized. Depending on the cell type, specific experimental conditions in vitro, cancer type and stage, galectin-3 has been reported to be exclusively cytoplasmic, predominantly nuclear or distributed between the two compartments. In this review we have summarized the dynamics of galectin-3 shuttling between the nucleus and the cytoplasm, the nuclear transport mechanisms of galectin-3, how its specific interactions with the members of β-catenin signaling pathways affect tumor progression, and its implications as a therapeutic target. © 2014 Elsevier Ltd. Source

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