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    Nicholas Webster

    TitleProfessor In Residence
    SchoolUniversity of California, San Diego
    Address9500 Gilman Drive #0673
    CA La Jolla 92093
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      Collapse Overview 
      Collapse Overview
      My lab is interested in mechanisms of signal transduction and gene regulation in different developmental and disease contexts. One of the current projects is to analyze the role of alternative splicing in liver development, metabolism and disease. They have created hepatocyte-specific knockouts of the splicing factors SRSF1 and SRSF3. They have previously these factors regulate insulin receptor splicing and promote inclusion of a small cassette exon 11 in the C-terminus of the hormone-binding domain. Deletion of SRSF3 impairs splicing of selected RNA isoforms resulting in inhibition of hepatocyte maturation, impairment of lipid and glucose metabolism, and generation endoplasmic reticulum stress. These defects result in a continual regeneration phenotype with increased proliferation and apoptosis, cellular pleiomorphism, eventually leading to fibrosis and hepatocellular adenoma formation and progression to hepatocellular carcinoma that metastasizes to the lung. This knockout thus represents a valuable model for human HCC as many of the same genes are altered.
      Another goal of our research is to investigate how changes in GnRH pulse frequency alter gene expression and secretory function in pituitary gonadotropes. Much of the work is based on the application of genomic technologies to understand the changes in mRNA expression and cell phenotype during response to pulsatile hypothalamic stimulation. We have used these genomic approaches to generate models of regulation that we are in the process of testing experimentally. We are also investigating how metabolic derangements alter reproductive function through effects on hypothalamic-pituitary signaling.
      My lab is also investigating the effects of obesity on breast cancer initiation and progression. Mouse mammary tumor cells form larger, more aggressive tumors in obese mice. The same acceleration is seen with both genetic and diet-induced obesity. The mammary fat pad in the obese mouse expresses high levels of TNFa and we have shown that this cytokine stimulates cancer cell proliferation in vitro. The lab is studying how omega-3 fatty acids, which are anti-inflammatory, can reverse the obesity effect on breast cancer growth.

      Collapse Research 
      Collapse Research Activities and Funding
      ShEEP Request for Beckman-Coulter Optima XPN 100 Ultracentrifuge
      VA IS1BX004386Jan 1, 2018 - Sep 30, 2018
      Role: Principal Investigator
      Time-Restricted Feeding and Breast Cancer
      NIH/NCI R01CA196853Apr 1, 2016 - Mar 31, 2021
      Role: Principal Investigator
      SRSF3 Loss and Hepatocellular Carcinoma
      VA I01BX002709Jan 1, 2016 - Dec 31, 2019
      Role: Principal Investigator
      Alternative Splicing of the Insulin Receptor Gene
      VA I01BX000130Apr 1, 2010 - Mar 31, 2014
      Role: Principal Investigator
      GnRH signaling in LbetaT2 gonadotrope cells
      NIH/NICHD R01HD047400Jul 1, 2005 - Apr 30, 2011
      Role: Principal Investigator
      Combinatorial Approaches to Activators of the NGF Recep*
      NIH/NIA R03AG023191Dec 15, 2003 - Nov 30, 2005
      Role: Principal Investigator
      Comprehensive Biology: Exploiting the Yeast Genome
      NIH P41RR011823Sep 30, 1996 - Jun 30, 2016
      Role: Co-Investigator
      NIH/NIDDK R01DK044643Sep 30, 1992 - Sep 30, 1996
      Role: Principal Investigator

      Collapse Bibliographic 
      Collapse Publications
      Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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      1. Webster N. Alternative RNA Splicing in the Pathogenesis of Liver Disease. Front Endocrinol (Lausanne). 2017; 8:133. PMID: 28680417.
        View in: PubMed
      2. Wollam J, Mahata S, Riopel M, Hernandez-Carretero A, Biswas A, Bandyopadhyay GK, Chi NW, Eiden LE, Mahapatra NR, Corti A, Webster N, Mahata SK. Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion. Cell Tissue Res. 2017 Jun; 368(3):487-501. PMID: 28220294.
        View in: PubMed
      3. Tang K, Pasqua T, Biswas A, Mahata S, Tang J, Tang A, Bandyopadhyay GK, Sinha-Hikim AP, Chi NW, Webster N, Corti A, Mahata SK. Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice. J Endocrinol. 2017 Feb; 232(2):137-153. PMID: 27799464.
        View in: PubMed
      4. Chung H, Chou W, Sears DD, Patterson RE, Webster N, Ellies LG. Time-restricted feeding improves insulin resistance and hepatic steatosis in a mouse model of postmenopausal obesity. Metabolism. 2016 Dec; 65(12):1743-1754. PMID: 27832862.
        View in: PubMed
      5. Huang PP, Brusman LE, Iyer AK, Webster N, Mellon PL. A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1) Enhancer-Derived Noncoding RNA Regulates Gnrh1 Gene Expression in GnRH Neuronal Cell Models. PLoS One. 2016; 11(7):e0158597. PMID: 27389022.
        View in: PubMed
      6. Kauffman AS, Thackray VG, Ryan GE, Tolson KP, Glidewell-Kenney CA, Semaan SJ, Poling MC, Iwata N, Breen KM, Duleba AJ, Stener-Victorin E, Shimasaki S, Webster N, Mellon PL. A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice. Biol Reprod. 2015 Sep; 93(3):69. PMID: 26203175; PMCID: PMC4710190.
      7. Hernandez M, Leichtle A, Pak K, Webster N, Wasserman SI, Ryan AF. The transcriptome of a complete episode of acute otitis media. BMC Genomics. 2015 Apr 03; 16:259. PMID: 25888408; PMCID: PMC4394589.
      8. Sen S, Langiewicz M, Jumaa H, Webster N. Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice. Hepatology. 2015 Jan; 61(1):171-83. PMID: 25132062; PMCID: PMC4280350.
      9. Schwaederle M, Parker BA, Schwab RB, Fanta PT, Boles SG, Daniels GA, Bazhenova LA, Subramanian R, Coutinho AC, Ojeda-Fournier H, Datnow B, Webster N, Lippman SM, Kurzrock R. Molecular tumor board: the University of California-San Diego Moores Cancer Center experience. Oncologist. 2014 Jun; 19(6):631-6. PMID: 24797821; PMCID: PMC4041669.
      10. Sharma S, Morinaga H, Hwang V, Fan W, Fernandez MO, Varki N, Olefsky JM, Webster N. Free fatty acids induce Lhb mRNA but suppress Fshb mRNA in pituitary LßT2 gonadotropes and diet-induced obesity reduces FSH levels in male mice and disrupts the proestrous LH/FSH surge in female mice. Endocrinology. 2013 Jun; 154(6):2188-99. PMID: 23525221; PMCID: PMC3740488.
      11. Talukdar I, Sen S, Urbano R, Thompson J, Yates JR, Webster N. hnRNP A1 and hnRNP F modulate the alternative splicing of exon 11 of the insulin receptor gene. PLoS One. 2011; 6(11):e27869. PMID: 22132154; PMCID: PMC3223206.
      12. Mistry DS, Tsutsumi R, Fernandez M, Sharma S, Cardenas SA, Lawson MA, Webster N. Gonadotropin-releasing hormone pulse sensitivity of follicle-stimulating hormone-beta gene is mediated by differential expression of positive regulatory activator protein 1 factors and corepressors SKIL and TGIF1. Mol Endocrinol. 2011 Aug; 25(8):1387-403. PMID: 21659477; PMCID: PMC3146254.
      13. Lan D, Lu M, Sharma S, Mellon PL, Olefsky JM, Webster N. Trans-resveratrol inhibits phosphorylation of Smad2/3 and represses FSHß gene expression by a SirT1-independent pathway in LßT2 gonadotrope cells. Reprod Toxicol. 2011 Jul; 32(1):85-92. PMID: 21679764; PMCID: PMC3155991.
      14. Lu M, Sarruf DA, Talukdar S, Sharma S, Li P, Bandyopadhyay G, Nalbandian S, Fan W, Gayen JR, Mahata SK, Webster N, Schwartz MW, Olefsky JM. Brain PPAR-? promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med. 2011 May; 17(5):618-22. PMID: 21532596; PMCID: PMC3380629.
      15. Godoy J, Nishimura M, Webster N. Gonadotropin-releasing hormone induces miR-132 and miR-212 to regulate cellular morphology and migration in immortalized LbetaT2 pituitary gonadotrope cells. Mol Endocrinol. 2011 May; 25(5):810-20. PMID: 21372146; PMCID: PMC3082323.
      16. Sharma S, Sharma PM, Mistry DS, Chang RJ, Olefsky JM, Mellon PL, Webster N. PPARG regulates gonadotropin-releasing hormone signaling in LbetaT2 cells in vitro and pituitary gonadotroph function in vivo in mice. Biol Reprod. 2011 Mar; 84(3):466-75. PMID: 21076077; PMCID: PMC3043129.
      17. Nguyen KA, Intriago RE, Upadhyay HC, Santos SJ, Webster N, Lawson MA. Modulation of gonadotropin-releasing hormone-induced extracellular signal-regulated kinase activation by dual-specificity protein phosphatase 1 in LbetaT2 gonadotropes. Endocrinology. 2010 Oct; 151(10):4882-93. PMID: 20685880; PMCID: PMC2946148.
      18. Sen S, Talukdar I, Liu Y, Tam J, Reddy S, Webster N. Muscleblind-like 1 (Mbnl1) promotes insulin receptor exon 11 inclusion via binding to a downstream evolutionarily conserved intronic enhancer. J Biol Chem. 2010 Aug 13; 285(33):25426-37. PMID: 20519504; PMCID: PMC2919106.
      19. Tsutsumi R, Mistry D, Webster N. Signaling responses to pulsatile gonadotropin-releasing hormone in LbetaT2 gonadotrope cells. J Biol Chem. 2010 Jun 25; 285(26):20262-72. PMID: 20406815; PMCID: PMC2888439.
      20. Leichtle A, Hernandez M, Pak K, Webster N, Wasserman SI, Ryan AF. The toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery. BMC Immunol. 2009 Aug 05; 10:45. PMID: 19656404; PMCID: PMC2736931.
      21. Tsutsumi R, Webster N. GnRH pulsatility, the pituitary response and reproductive dysfunction. Endocr J. 2009; 56(6):729-37. PMID: 19609045; PMCID: PMC4307809.
      22. Leichtle A, Hernandez M, Pak K, Yamasaki K, Cheng CF, Webster N, Ryan AF, Wasserman SI. TLR4-mediated induction of TLR2 signaling is critical in the pathogenesis and resolution of otitis media. Innate Immun. 2009 Aug; 15(4):205-15. PMID: 19586996; PMCID: PMC3565845.
      23. Webster N, Pirrung MC. Small molecule activators of the Trk receptors for neuroprotection. BMC Neurosci. 2008 Dec 03; 9 Suppl 2:S1. PMID: 19090982; PMCID: PMC2604901.
      24. Sen S, Talukdar I, Webster N. SRp20 and CUG-BP1 modulate insulin receptor exon 11 alternative splicing. Mol Cell Biol. 2009 Feb; 29(3):871-80. PMID: 19047369; PMCID: PMC2630670.
      25. Chandrasekar B, Boylston WH, Venkatachalam K, Webster N, Prabhu SD, Valente AJ. Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-kappaB/PTEN suppression. J Biol Chem. 2008 Sep 05; 283(36):24889-98. PMID: 18632660; PMCID: PMC3259831.
      26. Pirrung MC, Deng L, Lin B, Webster N. Quinone replacements for small molecule insulin mimics. Chembiochem. 2008 Feb 15; 9(3):360-2. PMID: 18232038.
        View in: PubMed
      27. Lu M, Tang Q, Olefsky JM, Mellon PL, Webster N. Adiponectin activates adenosine monophosphate-activated protein kinase and decreases luteinizing hormone secretion in LbetaT2 gonadotropes. Mol Endocrinol. 2008 Mar; 22(3):760-71. PMID: 18006641; PMCID: PMC2262174.
      28. Lin B, Li Z, Park K, Deng L, Pai A, Zhong L, Pirrung MC, Webster N. Identification of novel orally available small molecule insulin mimetics. J Pharmacol Exp Ther. 2007 Nov; 323(2):579-85. PMID: 17687071.
        View in: PubMed
      29. Pirrung MC, Li Z, Hensley E, Liu Y, Tanksale A, Lin B, Pai A, Webster N. Parallel synthesis of indolylquinones and their cell-based insulin mimicry. J Comb Chem. 2007 Sep-Oct; 9(5):844-54. PMID: 17595147.
        View in: PubMed
      30. Lin B, Pirrung MC, Deng L, Li Z, Liu Y, Webster N. Neuroprotection by small molecule activators of the nerve growth factor receptor. J Pharmacol Exp Ther. 2007 Jul; 322(1):59-69. PMID: 17468299.
        View in: PubMed
      31. Lawson MA, Tsutsumi R, Zhang H, Talukdar I, Butler BK, Santos SJ, Mellon PL, Webster N. Pulse sensitivity of the luteinizing hormone beta promoter is determined by a negative feedback loop Involving early growth response-1 and Ngfi-A binding protein 1 and 2. Mol Endocrinol. 2007 May; 21(5):1175-91. PMID: 17299135; PMCID: PMC2932486.
      32. Chung WH, Pak K, Lin B, Webster N, Ryan AF. A PI3K pathway mediates hair cell survival and opposes gentamicin toxicity in neonatal rat organ of Corti. J Assoc Res Otolaryngol. 2006 Dec; 7(4):373-82. PMID: 17053865; PMCID: PMC2504631.
      33. Zhang H, Bailey JS, Coss D, Lin B, Tsutsumi R, Lawson MA, Mellon PL, Webster N. Activin modulates the transcriptional response of LbetaT2 cells to gonadotropin-releasing hormone and alters cellular proliferation. Mol Endocrinol. 2006 Nov; 20(11):2909-30. PMID: 16772531; PMCID: PMC2673912.
      34. Liu F, Ruiz MS, Austin DA, Webster N. Constitutively active Gq impairs gonadotropin-releasing hormone-induced intracellular signaling and luteinizing hormone secretion in LbetaT2 cells. Mol Endocrinol. 2005 Aug; 19(8):2074-85. PMID: 15878957.
        View in: PubMed
      35. Pirrung MC, Liu Y, Deng L, Halstead DK, Li Z, May JF, Wedel M, Austin DA, Webster N. Methyl scanning: total synthesis of demethylasterriquinone B1 and derivatives for identification of sites of interaction with and isolation of its receptor(s). J Am Chem Soc. 2005 Apr 06; 127(13):4609-24. PMID: 15796526.
        View in: PubMed
      36. Palacios SD, Pak K, Rivkin AZ, Kayali AG, Austen D, Aletsee C, Melhus A, Webster N, Ryan AF. Role of p38 mitogen-activated protein kinase in middle ear mucosa hyperplasia during bacterial otitis media. Infect Immun. 2004 Aug; 72(8):4662-7. PMID: 15271927; PMCID: PMC470656.
      37. Webster N, Evans LG, Caples M, Erker L, Chew SL. Assembly of splicing complexes on exon 11 of the human insulin receptor gene does not correlate with splicing efficiency in-vitro. BMC Mol Biol. 2004 Jul 02; 5:7. PMID: 15233842; PMCID: PMC481066.
      38. Liu F, Austin DA, Webster N. Gonadotropin-releasing hormone-desensitized LbetaT2 gonadotrope cells are refractory to acute protein kinase C, cyclic AMP, and calcium-dependent signaling. Endocrinology. 2003 Oct; 144(10):4354-65. PMID: 12960037.
        View in: PubMed
      39. Webster N, Park K, Pirrung MC. Signaling effects of demethylasterriquinone B1, a selective insulin receptor modulator. Chembiochem. 2003 May 09; 4(5):379-85. PMID: 12740809.
        View in: PubMed
      40. Palacios SD, Pak K, Kayali AG, Rivkin AZ, Aletsee C, Melhus A, Webster N, Ryan AF. Participation of Ras and extracellular regulated kinase in the hyperplastic response of middle-ear mucosa during bacterial otitis media. J Infect Dis. 2002 Dec 15; 186(12):1761-9. PMID: 12447762.
        View in: PubMed
      41. Kayali AG, Austin DA, Webster N. Rottlerin inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation. Endocrinology. 2002 Oct; 143(10):3884-96. PMID: 12239100.
        View in: PubMed
      42. Vasilyev VV, Lawson MA, Dipaolo D, Webster N, Mellon PL. Different signaling pathways control acute induction versus long-term repression of LHbeta transcription by GnRH. Endocrinology. 2002 Sep; 143(9):3414-26. PMID: 12193554; PMCID: PMC2932485.
      43. Liu F, Usui I, Evans LG, Austin DA, Mellon PL, Olefsky JM, Webster N. Involvement of both G(q/11) and G(s) proteins in gonadotropin-releasing hormone receptor-mediated signaling in L beta T2 cells. J Biol Chem. 2002 Aug 30; 277(35):32099-108. PMID: 12050161; PMCID: PMC2930616.
      44. Seely BL, Samimi G, Webster N. Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in-vivo. BMC Cancer. 2002 May 31; 2:15. PMID: 12057025; PMCID: PMC115841.
      45. Vasilyev VV, Pernasetti F, Rosenberg SB, Barsoum MJ, Austin DA, Webster N, Mellon PL. Transcriptional activation of the ovine follicle-stimulating hormone-beta gene by gonadotropin-releasing hormone involves multiple signal transduction pathways. Endocrinology. 2002 May; 143(5):1651-9. PMID: 11956146; PMCID: PMC2930615.
      46. Liu F, Austin DA, Mellon PL, Olefsky JM, Webster N. GnRH activates ERK1/2 leading to the induction of c-fos and LHbeta protein expression in LbetaT2 cells. Mol Endocrinol. 2002 Mar; 16(3):419-34. PMID: 11875099.
        View in: PubMed
      47. Eichhorn J, Kayali AG, Resor L, Austin DA, Rose DW, Webster N. PLC-gamma1 enzyme activity is required for insulin-induced DNA synthesis. Endocrinology. 2002 Feb; 143(2):655-64. PMID: 11796522.
        View in: PubMed
      48. Webster N, Huang Z. Hormonal regulation of alternative splicing. Front Horm Res. 1999; 25:1-17. PMID: 10941399.
        View in: PubMed
      49. Webster N, Kong Y, Sharma P, Haas M, Sukumar S, Seely BL. Differential effects of Wilms tumor WT1 splice variants on the insulin receptor promoter. Biochem Mol Med. 1997 Dec; 62(2):139-50. PMID: 9441865.
        View in: PubMed
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