Browsing by Subject "Metabolic Networks and Pathways"

Now showing 1 - 8 of 8
  • Thumbnail Image
    ItemOpen Access
    An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.
    (Nature genetics, 2018-02) Chen, Ming; Zhang, Jiangwen; Sampieri, Katia; Clohessy, John G; Mendez, Lourdes; Gonzalez-Billalabeitia, Enrique; Liu, Xue-Song; Lee, Yu-Ru; Fung, Jacqueline; Katon, Jesse M; Menon, Archita Venugopal; Webster, Kaitlyn A; Ng, Christopher; Palumbieri, Maria Dilia; Diolombi, Moussa S; Breitkopf, Susanne B; Teruya-Feldstein, Julie; Signoretti, Sabina; Bronson, Roderick T; Asara, John M; Castillo-Martin, Mireia; Cordon-Cardo, Carlos; Pandolfi, Pier Paolo
    Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.
  • Thumbnail Image
    ItemOpen Access
    Caulobacter crescentus Adapts to Phosphate Starvation by Synthesizing Anionic Glycoglycerolipids and a Novel Glycosphingolipid.
    (mBio, 2019-04-02) Stankeviciute, Gabriele; Guan, Ziqiang; Goldfine, Howard; Klein, Eric A
    Caulobacter crescentus adapts to phosphate starvation by elongating its cell body and a polar stalk structure. The stalk is an extension of the Gram-negative envelope containing inner and outer membranes as well as a peptidoglycan cell wall. Cellular elongation requires a 6- to 7-fold increase in membrane synthesis, yet phosphate limitation would preclude the incorporation of additional phospholipids. In the place of phospholipids, C. crescentus can synthesize several glycolipid species, including a novel glycosphingolipid (GSL-2). While glycosphingolipids are ubiquitous in eukaryotes, the presence of GSL-2 in C. crescentus is surprising since GSLs had previously been found only in Sphingomonas species, in which they play a role in outer membrane integrity. In this paper, we identify three proteins required for GSL-2 synthesis: CcbF catalyzes the first step in ceramide synthesis, while Sgt1 and Sgt2 sequentially glycosylate ceramides to produce GSL-2. Unlike in Sphingomonas, GSLs are nonessential in C. crescentus; however, the presence of ceramides does contribute to phage resistance and susceptibility to the cationic antimicrobial peptide polymyxin B. The identification of a novel lipid species specifically produced upon phosphate starvation suggests that bacteria may be able to synthesize a wider variety of lipids in response to stresses than previously observed. Uncovering these lipids and their functional relevance will provide greater insight into microbial physiology and environmental adaptation.IMPORTANCE Bacteria adapt to environmental changes in a variety of ways, including altering their cell shape. Caulobacter crescentus adapts to phosphate starvation by elongating its cell body and a polar stalk structure containing both inner and outer membranes. While we generally think of cellular membranes being composed largely of phospholipids, cellular elongation occurs when environmental phosphate, and therefore phospholipid synthesis, is limited. In order to adapt to these environmental constraints, C. crescentus synthesizes several glycolipid species, including a novel glycosphingolipid. This finding is significant because glycosphingolipids, while ubiquitous in eukaryotes, are extremely rare in bacteria. In this paper, we identify three proteins required for GSL-2 synthesis and demonstrate that they contribute to phage resistance. These findings suggest that bacteria may synthesize a wider variety of lipids in response to stresses than previously observed.
  • Thumbnail Image
    ItemOpen Access
    Environmental conditions influence the plant functional diversity effect on potential denitrification.
    (PLoS One, 2011-02-02) Sutton-Grier, Ariana E; Wright, Justin P; McGill, Bonnie M; Richardson, Curtis
    Global biodiversity loss has prompted research on the relationship between species diversity and ecosystem functioning. Few studies have examined how plant diversity impacts belowground processes; even fewer have examined how varying resource levels can influence the effect of plant diversity on microbial activity. In a field experiment in a restored wetland, we examined the role of plant trait diversity (or functional diversity, (FD)) and its interactions with natural levels of variability of soil properties, on a microbial process, denitrification potential (DNP). We demonstrated that FD significantly affected microbial DNP through its interactions with soil conditions; increasing FD led to increased DNP but mainly at higher levels of soil resources. Our results suggest that the effect of species diversity on ecosystem functioning may depend on environmental factors such as resource availability. Future biodiversity experiments should examine how natural levels of environmental variability impact the importance of biodiversity to ecosystem functioning.
  • Thumbnail Image
    ItemOpen Access
    Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.
    (PLoS Genet, 2010-09-02) Chen, JL; Merl, D; West, M; Chi, JTA
    Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the "anti-Warburg" metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers.
  • Thumbnail Image
    ItemOpen Access
    Metabolic cross-talk allows labeling of O-linked beta-N-acetylglucosamine-modified proteins via the N-acetylgalactosamine salvage pathway.
    (Proceedings of the National Academy of Sciences of the United States of America, 2011-02-07) Boyce, Michael; Carrico, Isaac S; Ganguli, Anjali S; Yu, Seok-Ho; Hangauer, Matthew J; Hubbard, Sarah C; Kohler, Jennifer J; Bertozzi, Carolyn R
    Hundreds of mammalian nuclear and cytoplasmic proteins are reversibly glycosylated by O-linked β-N-acetylglucosamine (O-GlcNAc) to regulate their function, localization, and stability. Despite its broad functional significance, the dynamic and posttranslational nature of O-GlcNAc signaling makes it challenging to study using traditional molecular and cell biological techniques alone. Here, we report that metabolic cross-talk between the N-acetylgalactosamine salvage and O-GlcNAcylation pathways can be exploited for the tagging and identification of O-GlcNAcylated proteins. We found that N-azidoacetylgalactosamine (GalNAz) is converted by endogenous mammalian biosynthetic enzymes to UDP-GalNAz and then epimerized to UDP-N-azidoacetylglucosamine (GlcNAz). O-GlcNAc transferase accepts UDP-GlcNAz as a nucleotide-sugar donor, appending an azidosugar onto its native substrates, which can then be detected by covalent labeling using azide-reactive chemical probes. In a proof-of-principle proteomics experiment, we used metabolic GalNAz labeling of human cells and a bioorthogonal chemical probe to affinity-purify and identify numerous O-GlcNAcylated proteins. Our work provides a blueprint for a wide variety of future chemical approaches to identify, visualize, and characterize dynamic O-GlcNAc signaling.
  • Thumbnail Image
    ItemOpen Access
    Prostatic alpha-linolenic acid (ALA) is positively associated with aggressive prostate cancer: a relationship which may depend on genetic variation in ALA metabolism.
    (PLoS One, 2012) Azrad, Maria; Zhang, Kui; Vollmer, Robin T; Madden, John; Polascik, Thomas J; Snyder, Denise C; Ruffin, Mack T; Moul, Judd W; Brenner, Dean; Hardy, Robert W; Demark-Wahnefried, Wendy
    Previous observational studies have reported associations between prostate cancer and alpha-linolenic acid (ALA). However, few investigations have been able to study this relationship prospectively and in well-controlled settings. Moreover, no studies have determined whether single nucleotide polymorphisms (SNPs) that influence ALA metabolism are associated with this common cancer. The purpose of this study was to explore associations between prostatic levels of ALA, SNPs and prostate cancer-specific biomarkers in samples collected from a previous randomized clinical trial conducted using a presurgical model and which tested the effects of flaxseed supplementation, a rich source of ALA, prior to prostatectomy (n = 134). Serum prostate-specific antigen (PSA) was determined and immunohistochemistry was used to assess tumor proliferation rate (Ki67). Prostatic ALA was determined with gas chromatography. Seven previously identified SNPs associated with delta-6 desaturase activity (rs99780, rs174537, rs174545, rs174572, rs498793, rs3834458 and rs968567) were tested for associations with prostatic ALA, PSA and Ki67. Despite consuming seven times more ALA per day, men in the flaxseed arm had similar amounts of prostatic ALA relative to men not consuming flaxseed. In unadjusted analysis, there were significant positive associations between prostatic ALA and PSA (ρ = 0.191, p = 0.028) and Ki67 (ρ = 0.186, p = 0.037). After adjusting for covariates (flaxseed, age, race, BMI and statin-use) the association between ALA and PSA remained (p = 0.004) but was slightly attenuated for Ki67 (p = 0.051). We did not observe associations between any of the SNPs studied and prostatic ALA; however, in models for PSA there was a significant interaction between rs498793 and ALA and for Ki67 there were significant interactions with ALA and rs99780 and rs174545. Independent and inverse associations were observed between rs174572 and Ki67. This study provides evidence that prostatic ALA, independent of the amount of ALA consumed, is positively associated with biomarkers of aggressive prostate cancer and that genetic variation may modify this relationship.
  • Thumbnail Image
    ItemOpen Access
    The Skp2 Pathway: A Critical Target for Cancer Therapy.
    (Seminars in cancer biology, 2020-12) Cai, Zhen; Moten, Asad; Peng, Danni; Hsu, Che-Chia; Pan, Bo-Syong; Manne, Rajeshkumar; Li, Hong-Yu; Lin, Hui-Kuan
    Strictly regulated protein degradation by ubiquitin-proteasome system (UPS) is essential for various cellular processes whose dysregulation is linked to serious diseases including cancer. Skp2, a well characterized component of Skp2-SCF E3 ligase complex, is able to conjugate both K48-linked ubiquitin chains and K63-linked ubiquitin chains on its diverse substrates, inducing proteasome mediated proteolysis or modulating the function of tagged substrates respectively. Overexpression of Skp2 is observed in various human cancers associated with poor survival and adverse therapeutic outcomes, which in turn suggests that Skp2 engages in tumorigenic activity. To that end, the oncogenic properties of Skp2 are demonstrated by various genetic mouse models, highlighting the potential of Skp2 as a target for tackling cancer. In this article, we will describe the downstream substrates of Skp2 as well as upstream regulators for Skp2-SCF complex activity. We will further summarize the comprehensive oncogenic functions of Skp2 while describing diverse strategies and therapeutic platforms currently available for developing Skp2 inhibitors.
  • Thumbnail Image
    ItemOpen Access
    Unprecedented loss of ammonia assimilation capability in a urease-encoding bacterial mutualist.
    (BMC Genomics, 2010-12-02) Williams, Laura E; Wernegreen, Jennifer J
    BACKGROUND: Blochmannia are obligately intracellular bacterial mutualists of ants of the tribe Camponotini. Blochmannia perform key nutritional functions for the host, including synthesis of several essential amino acids. We used Illumina technology to sequence the genome of Blochmannia associated with Camponotus vafer. RESULTS: Although Blochmannia vafer retains many nutritional functions, it is missing glutamine synthetase (glnA), a component of the nitrogen recycling pathway encoded by the previously sequenced B. floridanus and B. pennsylvanicus. With the exception of Ureaplasma, B. vafer is the only sequenced bacterium to date that encodes urease but lacks the ability to assimilate ammonia into glutamine or glutamate. Loss of glnA occurred in a deletion hotspot near the putative replication origin. Overall, compared to the likely gene set of their common ancestor, 31 genes are missing or eroded in B. vafer, compared to 28 in B. floridanus and four in B. pennsylvanicus. Three genes (queA, visC and yggS) show convergent loss or erosion, suggesting relaxed selection for their functions. Eight B. vafer genes contain frameshifts in homopolymeric tracts that may be corrected by transcriptional slippage. Two of these encode DNA replication proteins: dnaX, which we infer is also frameshifted in B. floridanus, and dnaG. CONCLUSIONS: Comparing the B. vafer genome with B. pennsylvanicus and B. floridanus refines the core genes shared within the mutualist group, thereby clarifying functions required across ant host species. This third genome also allows us to track gene loss and erosion in a phylogenetic context to more fully understand processes of genome reduction.