Roger J Davis

Howard Hughes Medical Institute, Ashburn, Virginia, United States

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Publications (219)2376.09 Total impact

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    ABSTRACT: The role of ERβ in prostate cancer is unclear, although loss of ERβ is associated with aggressive disease. Given that mice deficient in ERβ do not develop prostate cancer, we hypothesized that ERβ loss occurs as a consequence of tumorigenesis caused by other oncogenic mechanisms and that its loss is necessary for tumorigenesis. In support of this hypothesis, we found that ERβ is targeted for repression in prostate cancer caused by PTEN deletion and that loss of ERβ is important for tumor formation. ERβ transcription is repressed by BMI-1, which is induced by PTEN deletion and important for prostate tumorigenesis. This finding provides a mechanism for how ERβ expression is regulated in prostate cancer. Repression of ERβ contributes to tumorigenesis because it enables HIF-1/VEGF signaling that sustains BMI-1 expression. These data reveal a positive feedback loop that is activated in response to PTEN loss and sustains BMI-1. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; DOI:10.1016/j.celrep.2015.02.063 · 7.21 Impact Factor
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    ABSTRACT: Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin's ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; DOI:10.1016/j.cell.2015.01.012 · 33.12 Impact Factor
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    ABSTRACT: Axonal death disrupts functional connectivity of neural circuits and is a critical feature of many neurodegenerative disorders. Pathological axon degeneration often occurs independently of known programmed death pathways, but the underlying molecular mechanisms remain largely unknown. Using traumatic injury as a model, we systematically investigate mitogen-activated protein kinase (MAPK) families and delineate a MAPK cascade that represents the early degenerative response to axonal injury. The adaptor protein Sarm1 is required for activation of this MAPK cascade, and this Sarm1-MAPK pathway disrupts axonal energy homeostasis, leading to ATP depletion before physical breakdown of damaged axons. The protective cytoNmnat1/Wld(s) protein inhibits activation of this MAPK cascade. Further, MKK4, a key component in the Sarm1-MAPK pathway, is antagonized by AKT signaling, which modulates the degenerative response by limiting activation of downstream JNK signaling. Our results reveal a regulatory mechanism that integrates distinct signals to instruct pathological axon degeneration. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (1). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38α mitogen activated protein kinase (MAPK) in ectodermal appendages using K14-cre mice (p38αK14 mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel due to defects in ameloblast differentiation and activity. In the absence of p38α, expression of amelogenin and β4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects implying that MKK6 functions as an upstream kinase of p38α in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38α functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38α MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 11/2014; 290(1). DOI:10.1074/jbc.M114.599274 · 4.60 Impact Factor
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    ABSTRACT: Liver regeneration is controlled by a complex network of signaling molecules and a prominent role for c-jun N-terminal kinase has been suggested during this process. In the present study we aimed to characterize and define the cell-type specific contribution of JNK1 activation during liver regeneration. We used hepatocyte-specific JNK1 knockout mice (JNK1Deltahepa) using the cre/lox-P system. We performed partial hepatectomy (PH) in WT, JNK1Deltahepa and JNK1-/- animals and investigated time-points up to 72h after PH. Additionally, bone marrow transplantation experiments were conducted in order to identify the contribution of hematopoietic cell-derived JNK1 activation for liver regeneration. Our results show that liver regeneration was significantly impaired in JNK1-/- compared to JNK1Deltahepa and WT animals. These data were evidenced by lower BrdU incorporation and decreased cell cycle markers such as Cyclin A, Cyclin D, E2F1 and PCNA 48h after PH in JNK1-/- compared with JNK1Deltahepa and WT livers. In JNK1-/- mice our findings were associated with a reduced acute phase response as evidenced by a lower activation of the IL-6/STAT3/SAA-1 cascade. Additionally, CD11b+Ly6G+-cells were decreased in JNK1-/- compared with JNK1Deltahepa and WT animals after PH. Transplantation of bone marrow-derived JNK1-/- into WT recipients caused significant reduction in liver regeneration. Interestingly, the transplantation of JNK1-/- into mice lacking JNK1 in hepatocytes only partially delayed liver regeneration. In summary, we provide evidence that (1) JNK1 in hematopoietic cells is crucial for liver regeneration and (2) a synergistic function between JNK1 in hepatocytes and hematopoietic-derived cells is involved in the hepatic regenerative response.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 10/2014; 1852(1-1):137-145. DOI:10.1016/j.bbadis.2014.10.011 · 5.09 Impact Factor
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    ABSTRACT: The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα). Therefore, JNK causes decreased expression of PPARα target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPARα target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARα-FGF21 hormone axis suppresses the metabolic effects of JNK deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver.
    Cell Metabolism 09/2014; 20(3). DOI:10.1016/j.cmet.2014.06.010 · 16.75 Impact Factor
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    ABSTRACT: Alzheimer's β-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1), however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both fast-velocity (∼2.7 μm/s) and high-frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (∼1.83 μm/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function located in the central region of JIP1b that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11-amino-acid C-terminal (C11) region with the tetratrico-peptide repeat of KLC1. High-frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast-velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr(668), a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons is mediated by novel roles of JIP1b.
    Molecular Biology of the Cell 08/2014; DOI:10.1091/mbc.E14-06-1111 · 4.55 Impact Factor
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    ABSTRACT: Chronic liver injury triggers complications such as liver fibrosis and hepatocellular carcinoma (HCC), which are associated with alterations in distinct signaling pathways. Of particular interest is the interaction between mechanisms controlled by IKKγ/NEMO, the regulatory IKK subunit, and Jnk activation for directing cell death and survival. In the present study, we aimed to define the relevance of Jnk in hepatocyte-specific NEMO knockout mice (NEMO(Δhepa)), a genetic model of chronic inflammatory liver injury.
    Journal of Hepatology 08/2014; 62(1). DOI:10.1016/j.jhep.2014.08.029 · 10.40 Impact Factor
  • Guadalupe Sabio, Roger J. Davis
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    ABSTRACT: The binding of tumour necrosis factor α (TNFα) to cell surface receptors engages multiple signal transduction pathways, including three groups of mitogen-activated protein (MAP) kinases: extracellular-signal-regulated kinases (ERKs); the cJun NH2-terminal kinases (JNKs); and the p38 MAP kinases. These MAP kinase signalling pathways induce a secondary response by increasing the expression of several inflammatory cytokines (including TNFα) that contribute to the biological activity of TNFα. MAP kinases therefore function both upstream and down-stream of signalling by TNFα receptors. Here we review mechanisms that mediate these actions of MAP kinases during the response to TNFα.
    Seminars in Immunology 06/2014; DOI:10.1016/j.smim.2014.02.009 · 6.12 Impact Factor
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    ABSTRACT: The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans, MKNK2, the gene encoding for Mnk2, is alternatively spliced yielding two splicing isoforms with differing last exons: Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38α-MAPK into the nucleus, leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation. Alternatively, Mnk2b is pro-oncogenic and does not activate p38-MAPK, while still enhancing eIF4E phosphorylation. We further show that Mnk2a colocalization with p38α-MAPK in the nucleus is both required and sufficient for its tumor-suppressive activity. Thus, Mnk2a downregulation by alternative splicing is a tumor suppressor mechanism that is lost in some breast, lung, and colon tumors.
    Cell Reports 04/2014; DOI:10.1016/j.celrep.2014.03.041 · 7.21 Impact Factor
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    ABSTRACT: The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of KrasG12D with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of KrasG12D-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonising the metaplastic conversion of acinar cells towards a ductal fate capable of responding to oncogenic stimulation.
    Cancer Research 04/2014; 74(12). DOI:10.1158/0008-5472.CAN-13-2941 · 9.28 Impact Factor
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    ABSTRACT: The cJun N-terminal kinase (JNK) signaling pathway is a key mediator of metabolic stress responses caused by consuming a high-fat diet, including the development of obesity. To test the role of JNK, we examined diet-induced obesity in mice with targeted ablation of Jnk genes in the anterior pituitary gland. These mice exhibited an increase in the pituitary expression of thyroid-stimulating hormone (TSH), an increase in the blood concentration of thyroid hormone (T4), increased energy expenditure, and markedly reduced obesity compared with control mice. The increased amount of pituitary TSH was caused by reduced expression of type 2 iodothyronine deiodinase (Dio2), a gene that is required for T4-mediated negative feedback regulation of TSH expression. These data establish a molecular mechanism that accounts for the regulation of energy expenditure and the development of obesity by the JNK signaling pathway.
    Genes & development 11/2013; 27(21):2345-55. DOI:10.1101/gad.223800.113 · 12.64 Impact Factor
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    ABSTRACT: Diet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-α, hypoxia, dexamethasone, high insulin, and a combination of TNF-α and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice. We found that different in vitro models capture distinct features of DIO adipose insulin resistance, and a combined treatment of TNF-α and hypoxia is most able to mimic the in vivo changes. Using genome-wide DNase I hypersensitivity followed by sequencing, we further examined the transcriptional regulation of TNF-α-induced insulin resistance, and we found that C/EPBβ is a potential key regulator of adipose insulin resistance.
    Cell Reports 10/2013; DOI:10.1016/j.celrep.2013.08.039 · 7.21 Impact Factor
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    ABSTRACT: The c-Jun N-terminal kinase-1 (Jnk1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and define the cell type involved in mediating the Jnk1-dependent effect on liver fibrogenesis. Jnk1(f/f) wildtype (WT), Jnk1(-/-) and Jnk1(Δhepa) (hepatocyte-specific deletion of Jnk1) mice were subjected to (i) bile duct ligation (BDL) and (ii) CCl4-induced liver fibrosis. Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs), studied their activation in vitro and investigated human diseased liver samples. Phosphorylated Jnk was expressed in myofibroblasts, epithelial and inflammatory cells during the progression of fibrogenesis in humans and mice. In mice, liver transaminases, alkaline phosphatase, bilirubin and liver histology revealed reduced injury in Jnk1(-/-) compared with WT and Jnk1(Δhepa) mice correlating with lower hepatocyte cell death and proliferation. Consequently, parameters of liver fibrosis such as Sirius red staining and collagen IA1 and α-smooth muscle actin expression were downregulated in Jnk1(-/-) compared with WT and Jnk1(Δhepa) livers, 4 weeks after CCl4 or BDL. BMT experiments excluded bone marrow-derived cells from having a major impact on the Jnk1-dependent effect on fibrogenesis, while primary HSCs from Jnk1(-/-) livers showed reduced transdifferentiation and extracellular matrix production. Moreover, Jnk1 ablation caused a reduced lifespan and poor differentiation of HSCs into matrix-producing myofibroblasts. Jnk1 in HSCs, but not in hepatocytes, significantly contribute to liver fibrosis development, identifying Jnk1 in HSCs as a profibrotic kinase and a promising cell-directed target for liver fibrosis.
    Gut 09/2013; 63(7). DOI:10.1136/gutjnl-2013-305507 · 13.32 Impact Factor
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    ABSTRACT: Saturated free fatty acid (FFA) is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK) pathway that activates cJun NH2-terminal kinase (JNK). Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that lack expression of MLK2 and MLK3. MLK deficiency protected mice against high-fat-diet-induced insulin resistance and obesity. Reduced JNK activation and increased energy expenditure contribute to the metabolic effects of MLK deficiency. These data confirm that the MLK pathway plays a critical role in the metabolic response to obesity.
    Cell Reports 08/2013; DOI:10.1016/j.celrep.2013.07.019 · 7.21 Impact Factor
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    ABSTRACT: This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1, AIIB2, in a xenograft model. The role of β1 integrins and of a β1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that β1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of β1 on resistance to radiation in vitro and in vivo. Finally, given the established cross-talk between β1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate β1 integrin levels. We report that IGF-IR regulates the expression of β1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 07/2013; 228(7). DOI:10.1002/jcp.24323 · 3.87 Impact Factor
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    ABSTRACT: We demonstrate that JNK responds to substrate stiffness and regulates AJ formation in epithelial cells in 2D cultures and in 3D tissues in vitro and in vivo. Rigid substrates led to JNK activation and AJ disassembly, while soft matrices suppressed JNK activity leading to AJ formation. Expression of constitutively active JNK (MKK7-JNK1) induced AJ dissolution even on soft substrates, while JNK knockdown (shJNK) induced AJ formation even on hard substrates. In human epidermis, basal cells expressed phosphorylated (p)-JNK but lacked AJ, while suprabasal keratinocytes contained strong AJ but lacked p-JNK. AJ formation was significantly impaired even in the upper suprabasal layers of bioengineered epidermis when prepared with stiffer scaffold or MKK7-JNK1 expressing keratinocytes. In contrast, shJNK1 or shJNK2 epidermis exhibited strong AJ even in the basal layer. The results with bioengineered epidermis were in full agreement with the epidermis of jnk1(-/-) or jnk2(-/-) mice. In conclusion, we propose that JNK mediates the effects of substrate stiffness on AJ formation in 2D and 3D context in vitro as well as in vivo.
    Journal of Cell Science 04/2013; 126(12). DOI:10.1242/jcs.122903 · 5.33 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS:: Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH) deficient mice are hypophagic, lean and do not develop hepatosteatosis when fed on high fat diet. Herein, we sought to investigate the role of melanin-concentrating hormone (MCH), an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area (LHA), on hepatic and adipocyte metabolism. METHODS:: Chronic central administration of MCH and adenoviral vectors increasing MCH signalling were performed in rats and mice. Vagal dennervation was done to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were assessed by real-time PCR and western blot. RESULTS:: We demonstrate that the activation of MCH receptors (MCH-R) promotes nonalcoholic fatty liver disease (NAFLD) through the parasympathetic nervous system (PSNS), whereas it increases fat deposition in WAT via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, being c-Jun N-terminal kinase (JNK1) an essential player, while in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH-R or infusion of MCH specifically in the LHA modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus (ARC) affected adipocyte metabolism. CONCLUSIONS:: Our findings reveal that central MCH directly controls hepatic and adipocyte metabolism through different pathways.
    Gastroenterology 03/2013; 144(3):636-649. DOI:10.1053/j.gastro.2012.10.051 · 13.93 Impact Factor
  • 03/2013; DOI:10.1530/endoabs.32.P681

Publication Stats

28k Citations
2,376.09 Total Impact Points

Institutions

  • 1992–2015
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1985–2015
    • University of Massachusetts Medical School
      • • Program in Molecular Medicine
      • • Department of Biochemistry and Molecular Pharmacology
      Worcester, Massachusetts, United States
  • 1993–2014
    • University of Massachusetts Amherst
      • Department of Biochemistry and Molecular Biology
      Amherst Center, Massachusetts, United States
  • 2001–2011
    • University of Vermont
      • • Department of Surgery
      • • Department of Medicine
      Burlington, VT, United States
    • Assumption College
      Worcester, Massachusetts, United States
  • 2010
    • Åbo Akademi University
      • Turku Centre for Biotechnology
      Turku, Varsinais-Suomi, Finland
  • 2009
    • Massachusetts Institute of Technology
      • Department of Biological Engineering
      Cambridge, Massachusetts, United States
  • 2003–2009
    • Yale University
      • Department of Immunobiology
      New Haven, Connecticut, United States
    • Roche
      Bâle, Basel-City, Switzerland
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
    • King's College London
      • Cardiovascular Division
      London, ENG, United Kingdom
  • 2008
    • University of Dundee
      • MRC Protein Phosphorylation Unit
      Dundee, SCT, United Kingdom
  • 2007
    • Albert Einstein College of Medicine
      • Department of Molecular Pharmacology
      New York City, NY, United States
  • 2006
    • University of California, Davis
      Davis, California, United States
  • 2005
    • Columbia University
      • Department of Pathology & Cell Biology
      New York, New York, United States
  • 2002–2005
    • University of Ottawa
      • Department of Cellular and Molecular Medicine
      Ottawa, Ontario, Canada
    • Stony Brook University
      • Department of Molecular Genetics and Microbiology
      Stony Brook, New York, United States
  • 2004
    • The University of Manchester
      • Faculty of Life Sciences
      Manchester, ENG, United Kingdom