A5048283029- Sphingolipid Metabolism and Signaling
- Autophagy in Disease and Therapy
- HIV Research and Treatment
- Immune Cell Function and Interaction
- PI3K/AKT/mTOR signaling in cancer
- Cancer, Hypoxia, and Metabolism
- Cellular transport and secretion
- Metabolism, Diabetes, and Cancer
- Calcium signaling and nucleotide metabolism
- T-cell and B-cell Immunology
- Lipid Membrane Structure and Behavior
- Amino Acid Enzymes and Metabolism
- Phagocytosis and Immune Regulation
- Cell death mechanisms and regulation
- HIV/AIDS drug development and treatment
- Crystallization and Solubility Studies
- RNA Interference and Gene Delivery
- HIV/AIDS Research and Interventions
- Caveolin-1 and cellular processes
- X-ray Diffraction in Crystallography
- Polyamine Metabolism and Applications
- Epigenetics and DNA Methylation
- Pancreatic function and diabetes
- Erythrocyte Function and Pathophysiology
- Toxoplasma gondii Research Studies
University of California, Irvine
2014-2024
New York Academy of Sciences
2020
John Wiley & Sons (United States)
2020
Hudson Institute
2020
Cancer Research Institute
2001-2005
University of Pennsylvania
1997-2005
UPMC Hillman Cancer Center
2001-2003
University of Louisville
1997
Université Libre de Bruxelles
1997
Johns Hopkins University
1997
In multicellular organisms, constituent cells depend on extracellular signals for growth, proliferation, and survival. When are withdrawn from growth factors, they undergo apoptosis. Expression of constitutively active forms the serine/threonine kinase Akt/PKB can prevent apoptosis upon factor withdrawal. Akt-mediated survival depends in part maintenance glucose metabolism, suggesting that reduced utilization contributes to withdrawal-induced death. However, it is unclear how restricting...
We report that PTEN-deficient prostate cancer cells use macropinocytosis to survive and proliferate under nutrient stress. PTEN loss increased only in the context of AMPK activation, revealing a general requirement for novel mechanism by which promotes survival In cells, albumin uptake did not require macropinocytosis, but necrotic cell debris proved specific macropinocytic cargo. Isotopic labeling confirmed macropinocytosed proteins fueled new protein synthesis cells. Supplementation with...
Abstract Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals necrocytosis provides not only acids, but sugars, fatty and nucleotides for biosynthesis, conferring resistance to therapies targeting pathways. Indeed, allow macropinocytic breast prostate proliferate, despite acid synthase inhibition....
Human immunodeficiency virus type 1 (HIV-1) requires both CD4 and a coreceptor to infect cells. Macrophage-tropic (M-tropic) HIV-1 strains utilize the chemokine receptor CCR5 in conjunction with cells, while T-cell-tropic (T-tropic) generally CXCR4 as coreceptor. Some viruses can use for entry (i.e., are dual-tropic), other receptors be used by subset of strains. Due genetic diversity HIV-1, HIV-2, simian (SIV) potential than or influence viral pathogenesis, we tested panel 28 SIV envelope...
A comparison of Akt- and Bcl-xL-dependent cell survival was undertaken using interleukin-3-dependent FL5.12 cells. Expression constitutively active Akt allows cells to survive for prolonged periods following growth factor withdrawal. This correlates with the expression level activated is comparable in magnitude protection provided by anti-apoptotic geneBcl-xL. Although both genes prevent death, Akt-protected can be distinguished fromBcl-xL-protected on basis increased glucose transporter...
Brain capillary endothelial cells (BCECs) are targets of CD4-independent infection by HIV-1 and simian immunodeficiency virus (SIV) strains in vitro vivo. Infection BCECs may provide a portal entry for the into central nervous system could disrupt blood-brain barrier function, contributing to development AIDS dementia. We found that rhesus macaque express chemokine receptors involved HIV SIV including CCR5, CCR3, CXCR4, STRL33, but not CCR2b, GPR1, or GPR15. neurovirulent strain SIV/17E-Fr...
Leukocyte chemoattractants act through a rapidly growing subfamily of G protein-coupled receptors. We report the cloning novel human gene encoding an orphan receptor (ChemR23) related to C3a, C5a and formyl Met-Leu-Phe receptors, more distantly subfamilies chemokine ChemR23 transcripts were found be abundant in monocyte-derived dendritic cells macrophages, treated or not with LPS. Low expression could also detected by reverse transcription-PCR CD4+ T lymphocytes. The was assigned radiation...
Certain chemokine receptors serve as cofactors for HIV type 1 envelope (env)-mediated cell–cell fusion and virus infection of CD4-positive cells. Macrophage tropic (M-tropic) HIV-1 isolates use CCR5, T cell (T-tropic) strains CXCR4. To investigate the used by simian immunodeficiency viruses (SIV), we tested four T-tropic two M-tropic SIV env proteins their ability to mediate with cells expressing CD4 either human or nonhuman primate receptors. Unlike HIV-1, both M- envs CCR5 but not CXCR4...
ABSTRACT Both CD4 and an appropriate coreceptor are necessary for infection of cells by human immunodeficiency virus type 1 (HIV-1) most strains HIV-2. The chemokine receptors CCR5 CXCR4 the major HIV-1 coreceptors, although some can also utilize alternative coreceptors such as CCR3 to infect cells. In contrast, if not all simian (SIV) use a coreceptor, many SIV independently CD4. addition, several orphan seven-transmembrane which serve have been identified. Here we report that APJ, domain...
Ceramide induces cell death in response to many stimuli. Its mechanism of action, however, is not completely understood. autophagy mammalian cells maintained rich media and nutrient permease downregulation yeast. These observations suggested us that ceramide might kill by limiting cellular access extracellular nutrients. Consistent with this proposal, physiologically relevant concentrations produced a profound specific transporter proteins cells. Blocking ceramide-induced loss or...
Human and simian immunodeficiency viruses (HIV SIV, respectively) use chemokine receptors as coreceptors along with CD4 to mediate viral entry. Several orphan receptors, including GPR1, GPR15, STRL33, can also serve for a more limited number of HIV SIV isolates. We investigated whether these could function efficient diverse group envelopes (Envs) in comparison the principal CCR5 CXCR4. found that HIV-1 isolates inefficient cell–cell fusion relative CXCR4; however, none tested support...
The small GTPase Rab7 promotes fusion events between late endosomes and lysosomes. activity is regulated by extrinsic signals, most likely via effects on its guanine nucleotide exchange factor (GEF) or GTPase-activating protein (GAP). Based their homology to the yeast proteins that regulate Ypt7 GTP binding state, TBC1D15, mammalian Vps39 (mVps39) have been suggested function as GAP GEF, respectively. We developed an effector pull-down assay test this model. TBC1D15 functioned a in cells,...
The BCL-2 family members BAK and BAX are required for apoptosis trigger mitochondrial outer membrane permeabilization (MOMP). Here we identify a MOMP-independent function of as factor long-chain ceramide production in response to pro-apoptotic stress. UV-C irradiation wild-type (WT) cells increased ceramides; blocking generation prevented caspase activation cell death, demonstrating that ceramides play key role UV-C-induced apoptosis. In contrast, did not increase double knock-out cells....
The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI(3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells delineate whether has additional roles endocytic trafficking. In Vps34-/- mouse embryonic fibroblasts (MEFs), transferrin recycling EEA1 localization were unaffected despite elevated Rab5-GTP levels. Strikingly, a large increase Rab7-GTP levels, an...
Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating macropinocytosis autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel access pathways have potential as powerful starvation agents. Here, we describe water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, triggers transporter...
ABSTRACT To investigate the basis for envelope (Env) determinants influencing simian immunodeficiency virus (SIV) tropism, we studied a number of Envs that are closely related to SIVmac239, pathogenic, T-tropic is neutralization resistant. The from macrophage-tropic (M-tropic) strains SIVmac316, 1A11, 17E-Fr, and 1100 facilitated infection CCR5-positive, CD4-negative cells. In contrast, SIVmac239 Env was strictly dependent upon presence CD4 membrane fusion. We also found M-tropic strains,...