Browsing by Author "Lin, Lin"

Now showing 1 - 3 of 3
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    Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells
    (Springer Nature, 2022) Halbrook, Christopher J.; Thurston, Galloway; Boyer, Seth; Anaraki, Cecily; Jiménez, Jennifer A.; McCarthy, Amy; Steele, Nina G.; Kerk, Samuel A.; Hong, Hanna S.; Lin, Lin; Law, Fiona V.; Felton, Catherine; Scipioni, Lorenzo; Sajjakulnukit, Peter; Andren, Anthony; Beutel, Alica K.; Singh, Rima; Nelson, Barbara S.; Van Den Bergh, Fran; Krall, Abigail S.; Mullen, Peter J.; Zhang, Li; Batra, Sandeep; Morton, Jennifer P.; Stanger, Ben Z.; Christofk, Heather R.; Digman, Michelle A.; Beard, Daniel A.; Viale, Andrea; Zhang, Ji; Crawford, Howard C.; di Magliano, Marina Pasca; Jorgensen, Claus; Lyssiotis, Costas A.; Pediatrics, School of Medicine
    The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG–asparaginase sensitizes tumors to mitochondrial targeting with phenformin.
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    Gentamicin Induced Intracellular Toxicity in Saccharomyces cerevisiae
    (2011-02) Lin, Lin; Goebl, Mark, 1958-; Harrington, Maureen A.; Bauer, Margaret E.; Wagner, Mark C.; Molitoris, Bruce A.
    At the present time, gentamicin is used in the treatment of both Gram-negative and Gram-positive bacterial infections. However, the poorly understood side effect of nephrotoxicity is a serious problem and is one of the dose-limiting factors in the use of gentamicin. In our model system, Saccharomyces cerevisiae, which is relatively resistant to gentamicin, at least 20 genes are required for gentamicin resistance. Inspection of the physical and genetic interactions of the gentamicin sensitive mutants reveals a network centered on the ARF pathway which plays a key role in the regulation of retrograde trafficking. Our studies show that arf1ts arf1Δ arf2Δ cells, gea1ts gea1Δ gea2Δ cells, and gcs1ts gcs1Δ glo3Δ cells are all hypersensitive to gentamicin which indicates that impaired Arf1 function causes yeast cells to become hypersensitive to gentamicin. As evidence, cellular CPY trafficking and processing are blocked by the presence of gentamicin in some of these mutants. Interestingly, gentamicin can directly affect the level of the GTP-bound form of Arf1 in a cell growth phase-dependent manner; even though total Arf1 levels in S. cerevisiae are not affected. As predicted, we also find that gentamicin-bound resin can enrich both yeast Arf1-TAP protein and rat Arf1 protein in vitro. With the help of mass spectrometry, we also generated a gentamicin-binding protein list. Gentamicin hypersensitivity is also observed in S. cerevisiae double deletion strains that lack both ARF1 and ARF2 but are kept alive by the presence of hARF4 or bARF1. Increased -1 programmed ribosomal frameshifting efficiency is also observed in cells treated with gentamicin. Finally, a comparison of a gentamicin mixture and four of the gentamicin congeners reveals that gentamicin C1 is less toxic than other gentamicin congeners or the gentamicin total mixture.
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    Inactivating hepatic follistatin alleviates hyperglycemia
    (Springer Nature, 2018-07) Tao, Rongya; Wang, Caixia; Stöhr, Oliver; Qiu, Wei; Hu, Yue; Miao, Ji; Dong, X. Charlie; Leng, Sining; Stefater, Margaret; Stylopoulos, Nicholas; Lin, Lin; Copps, Kyle D.; White, Morris F.; Biochemistry and Molecular Biology, School of Medicine
    Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)-even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines-including excess follistatin (Fst)-that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.