MODULATION OF IFN ACTION VIA NOVEL REGULATORY FACTORS

Summary

Principal Investigator: DHAN V KALVAKOLANU
Abstract: DESCRIPTION (provided by applicant): The interferon family of cytokines is critical for promoting several physiologic processes, such as antiviral, antitumor, and immune responses. They are in clinical use for the therapy of a number of cancers, viral diseases and neurodegenerative disorders. By interacting with other cytokines IFNs form a large network of intercellular signaling molecules that control neoplastic cell growth and host defenses against pathogens. Previously, we have identified a novel IFN-regulated element and its cognate transcription factors. One such protein is CCAAT/Enhancer Binding protein-beta (C/EBP-2), a transcription factor known to regulate cell differentiation, energy metabolism, immune response, tumor growth and apoptosis. A gene expression micro- array analysis in our lab identified several IFN regulated genes, whose expression required C/EBP-2. One of them is the death associated protein kinase1 (DAPK1), an important regulator of apoptosis, cell cycle, and metastasis. The expression of dapk1 gene is frequently lost in several human cancers. DAPK1 also regulates autophagy (a novel form of death), which is critical for the removal of damaged organelle, fighting intracellular pathogens, antigen presentation and tumor suppression. Interestingly, the loss of C/EBP-2 gene in mice causes many of these defects. During the last funding period, we have shown a central role for C/EBP-2 in regulating DAPK1. In preliminary studies, we show that the expression of DAPK1 requires other transacting factors. Notably, Activating transcription factor 6 (ATF6), a key regulator of endoplasmic reticulum-dependent stress responses, appears to regulate DAPK1 expression. We propose that a direct interaction between ATF6 and C/EBP-2 leads to DAPK1 expression and growth suppression via autophagy, wherein the MAP Kinase, apoptosis- stimulating kinase 1(ASK1), provides critical signal inputs. In specific aim 1 of this proposal we will investigate how C/EBP-2 and ATF6 collaborate to upregulate DAPK1 expression. In specific aim 2, we will investigate how ASK1 controls DAPK1 expression via ATF6. Enhancer bound transcription factors (TFs) promote transcription using transcriptional co-activators. One of them the Mediator, a molecular bridge comprised of multiple proteins, communicates the transcriptional signals from the TFs to general transcription factor complex at the TATA-box. Studies during the last funding period also identified Med1, a major subunit of Mediator, an IFN-induced binding partner of C/EBP- 2. We present preliminary evidence for the involvement of ZIP-kinase(ZIPK), a member of the DAPK family, in regulating DAPK1 expression in response to IFNs. We hypothesize that ZIPK regulates DAPK1 expression by modulating the phosphorylation of C/EBP-binding domain of Med1. This aspect will be investigated in specific aim 3. We will evaluate the critical relevance of these factors to DAPK1 and autophagy using RNAi, knockout mice, protein-interactions, ChIP assays, mutagenesis and transcriptional analyses. Knowledge gained from an understanding these pathways, will not only define the critical regulators of DAPK1, but also will provide indicators into how a loss of DAPK1 can occur. We will investigate the relevance of these pathways to human CLL, a disease in which dapk1 appears to play an important tumor suppressive role. These in turn will allow a better design of therapeutics to combat tumor progression and metastasis. PUBLIC HEALTH RELEVANCE: Tumor metastasis occurs due to a loss of certain critical genes and a suppression of corresponding biological processes. Studies proposed in this application will investigate the regulation of an anti-metastatic gene, DAPK1, which is critical for tumor suppression and autophagic responses.
Funding Period: 1998-09-16 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. ncbi A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression
    Qin Zhang
    Department of Environmental Health Sciences, Bloomberg School of Public Health and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA
    J Biol Chem 281:10174-81. 2006
  2. pmc Innate immunity against bacterial infection following hyperoxia exposure is impaired in NRF2-deficient mice
    Narsa M Reddy
    Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Room E7610, 615 North Wolfe Street, Baltimore, Maryland 21205, USA
    J Immunol 183:4601-8. 2009
  3. pmc STAT-phosphorylation-independent induction of interferon regulatory factor-9 by interferon-beta
    M R Sandhya Rani
    Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Interferon Cytokine Res 30:163-70. 2010
  4. pmc Cytokine-induced tumor suppressors: a GRIM story
    DHAN V KALVAKOLANU
    Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Cytokine 52:128-42. 2010
  5. pmc GRIM-19 and p16(INK4a) synergistically regulate cell cycle progression and E2F1-responsive gene expression
    Peng Sun
    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    J Biol Chem 285:27545-52. 2010
  6. pmc Identification and characterization of GRIM-1, a cell-death-associated gene product
    EDWARD R HOFMANN
    Greenebaum Cancer Center, Department of Microbiology and Immunology, Molecular and Cellular Cancer Biology Track, GPILS, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Cell Sci 123:2781-91. 2010
  7. pmc Enhanced tumor suppression in vitro and in vivo by co-expression of survivin-specific siRNA and wild-type p53 protein
    Y Shao
    Department of Pathophysiology, Norman Bethune College of Medicine and Prostate Diseases Prevention and Treatment Research Center, Jilin University, Changchun, China
    Cancer Gene Ther 17:844-54. 2010
  8. pmc GRIM-19 disrupts E6/E6AP complex to rescue p53 and induce apoptosis in cervical cancers
    Ying Zhou
    Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui, The People s Republic of China
    PLoS ONE 6:e22065. 2011
  9. pmc GRIM-1, a novel growth suppressor, inhibits rRNA maturation by suppressing small nucleolar RNAs
    Shreeram C Nallar
    Department of Microbiology and Immunology, University of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, United States of America
    PLoS ONE 6:e24082. 2011
  10. pmc A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia
    Rajasubramaniam Shanmugam
    Departments of Medicine Hematology Oncology Division and Biostatistics and Computational Biology, Indiana, USA
    Clin Cancer Res 18:360-9. 2012

Detail Information

Publications37

  1. ncbi A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression
    Qin Zhang
    Department of Environmental Health Sciences, Bloomberg School of Public Health and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA
    J Biol Chem 281:10174-81. 2006
    ....
  2. pmc Innate immunity against bacterial infection following hyperoxia exposure is impaired in NRF2-deficient mice
    Narsa M Reddy
    Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Room E7610, 615 North Wolfe Street, Baltimore, Maryland 21205, USA
    J Immunol 183:4601-8. 2009
    ..Thus, loss of Nrf2 impairs lung innate immunity and promotes susceptibility to bacterial infection after hyperoxia exposure, ultimately leading to death of the host...
  3. pmc STAT-phosphorylation-independent induction of interferon regulatory factor-9 by interferon-beta
    M R Sandhya Rani
    Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Interferon Cytokine Res 30:163-70. 2010
    ..These studies provide the first evidence that signaling pathways leading to gene transcription are activated by IFN-beta independent of STAT phosphorylation...
  4. pmc Cytokine-induced tumor suppressors: a GRIM story
    DHAN V KALVAKOLANU
    Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Cytokine 52:128-42. 2010
    ..In addition, GRIM-19 appears to participate in innate immune responses as its activity is modulated by several viruses and bacteria. Thus, GRIMs seem to couple with multiple biological responses by acting at critical nodes...
  5. pmc GRIM-19 and p16(INK4a) synergistically regulate cell cycle progression and E2F1-responsive gene expression
    Peng Sun
    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    J Biol Chem 285:27545-52. 2010
    ....
  6. pmc Identification and characterization of GRIM-1, a cell-death-associated gene product
    EDWARD R HOFMANN
    Greenebaum Cancer Center, Department of Microbiology and Immunology, Molecular and Cellular Cancer Biology Track, GPILS, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Cell Sci 123:2781-91. 2010
    ..Together, these studies identified a novel protein involved in growth suppression and cell death...
  7. pmc Enhanced tumor suppression in vitro and in vivo by co-expression of survivin-specific siRNA and wild-type p53 protein
    Y Shao
    Department of Pathophysiology, Norman Bethune College of Medicine and Prostate Diseases Prevention and Treatment Research Center, Jilin University, Changchun, China
    Cancer Gene Ther 17:844-54. 2010
    ....
  8. pmc GRIM-19 disrupts E6/E6AP complex to rescue p53 and induce apoptosis in cervical cancers
    Ying Zhou
    Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui, The People s Republic of China
    PLoS ONE 6:e22065. 2011
    ..The aims of this study were to determine the potential role of GRIM-19 in rescuing p53 protein and inducing cervical cancer cell apoptosis...
  9. pmc GRIM-1, a novel growth suppressor, inhibits rRNA maturation by suppressing small nucleolar RNAs
    Shreeram C Nallar
    Department of Microbiology and Immunology, University of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, United States of America
    PLoS ONE 6:e24082. 2011
    ..Consistent with its growth-suppressive property, GRIM-1 expression is lost in a number of human primary prostate tumors. Our observations support a recent study that GRIM-1 might act as a co-tumor suppressor in the prostate...
  10. pmc A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia
    Rajasubramaniam Shanmugam
    Departments of Medicine Hematology Oncology Division and Biostatistics and Computational Biology, Indiana, USA
    Clin Cancer Res 18:360-9. 2012
    ..A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis...
  11. pmc Chromatin immunoprecipitation assay as a tool for analyzing transcription factor activity
    Padmaja Gade
    Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
    Methods Mol Biol 809:85-104. 2012
    ..Further, the applications of ChIP assays for discovering novel genes that are dependent on specific transcription factors were addressed...
  12. pmc Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1
    Michelle Vaz
    Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
    Mol Cell Biol 32:1694-709. 2012
    ..Thus, Fra-1 appears to increase susceptibility to oxidants and promotes cell death by attenuating Nrf2-driven antioxidant responses...
  13. pmc Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC
    Y Tian
    Prostate Diseases Prevention and Treatment Research Centre and Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Changchun, People s Republic of China
    Cancer Gene Ther 19:393-401. 2012
    ..Cancer in these cured mice did not recur over 2 years following treatment. These data demonstrated that RNA interference combined with Salmonella as a delivery system may offer a novel clinical approach for cancer gene therapy...
  14. pmc An IFN-γ-stimulated ATF6-C/EBP-β-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy
    Padmaja Gade
    Department of Microbiology and Immunology, Center for Vaccine Development, and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Proc Natl Acad Sci U S A 109:10316-21. 2012
    ..These studies not only unravel an IFN signaling pathway that controls cell growth and antibacterial defense, but also expand the role of ATF6 beyond ER stress...
  15. pmc IFNG and autophagy: a critical role for the ER-stress mediator ATF6 in controlling bacterial infections
    Dhananjaya V Kalvakolanu
    Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
    Autophagy 8:1673-4. 2012
    ..More importantly, the Atf6(-/-) mice are highly susceptible to lethal bacterial infections due to a loss of autophagy. This study reported a connection between ER stress and autophagy in mediating antibacterial defenses...
  16. pmc Delivery of the co-expression plasmid pEndo-Si-Stat3 by attenuated Salmonella serovar typhimurium for prostate cancer treatment
    Xin Li
    Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Center, Norman Bethune Medical School, Jilin University, Xinmin Street, Changchun, 130021, People s Republic of China
    J Cancer Res Clin Oncol 139:971-80. 2013
    ..To investigate the therapeutic utility of an attenuated bacterium carrying a plasmid that co-expresses Endostatin, an inhibitor of tumor neovasculogenesis, and a shRNA that targets Stat3 to suppress prostate cancer growth...
  17. pmc The transcription factor C/EBP-β mediates constitutive and LPS-inducible transcription of murine SerpinB2
    Ekemini A Udofa
    Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
    PLoS ONE 8:e57855. 2013
    ..Together, these data provide new insight into C/EBP-β-dependent regulation of inflammation-associated SerpinB2 expression...
  18. pmc Down-regulation of GRIM-19 expression is associated with hyperactivation of STAT3-induced gene expression and tumor growth in human cervical cancers
    Ying Zhou
    Anhui Province Key Laboratory of Molecular Medicine and Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, People s Republic of China
    J Interferon Cytokine Res 29:695-703. 2009
    ..GRIM-19 suppressed the expression of tumor invasion- and angiogenesis-associated factors to limit tumor growth. This study identifies another major novel molecular pathway inactivated during the development of human cervical cancer...
  19. pmc A central role for transcription factor C/EBP-beta in regulating CD1d gene expression in human keratinocytes
    Hashmat Sikder
    Department of Dermatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Immunol 183:1657-66. 2009
    ..Together, these data show a central role for C/EBP-beta in regulating CD1d transcription...
  20. pmc Down-regulation of the transcriptional mediator subunit Med1 contributes to the loss of expression of metastasis-associated dapk1 in human cancers and cancer cells
    Padmaja Gade
    Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Int J Cancer 125:1566-74. 2009
    ..Our studies reveal a critical parameter limiting dapk1 expression in cancer cell lines...
  21. ncbi A role for Stat1 in the regulation of lipopolysaccharide-induced interleukin-1beta expression
    Vishwas D Joshi
    Department of Medicine, Division of Geographic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Interferon Cytokine Res 26:739-47. 2006
    ....
  22. pmc The IFN-beta and retinoic acid-induced cell death regulator GRIM-19 is upregulated during focal cerebral ischemia
    Zara Mehrabian
    Department of Anesthesiology, University of Maryland School of Medicine, 685 W Baltimore Street, Baltimore, MD 21201, USA
    J Interferon Cytokine Res 27:383-92. 2007
    ..These results suggest that GRIM-19 may play a role in ischemia-induced neuronal cell death...
  23. ncbi Intratumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs
    Ling Zhang
    Prostate Diseases Prevention and Treatment Research Centre and Department of Pathophysiology, School of Basic Medicine, Jilin University, Changchun, P R China
    Cancer Res 67:5859-64. 2007
    ..These results suggest that attenuated S. typhimurium combined with an RNA interference approach might be more effective for the treatment of primary as well as metastatic cancer...
  24. ncbi FRA-1 proto-oncogene induces lung epithelial cell invasion and anchorage-independent growth in vitro, but is insufficient to promote tumor growth in vivo
    Pavan Adiseshaiah
    Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
    Cancer Res 67:6204-11. 2007
    ..In contrast, FRA-1 failed to promote tumor formation by BEAS-2B. We suggest that FRA-1 can promote motility, invasion, and anchorage-independent growth of lung epithelial cells in vitro, but is insufficient for tumor formation...
  25. ncbi Tumor-suppressive activity of the cell death activator GRIM-19 on a constitutively active signal transducer and activator of transcription 3
    Sudhakar Kalakonda
    Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Cancer Res 67:6212-20. 2007
    ..In this study, we show that GRIM-19 suppresses constitutive STAT3-induced cellular transformation in vitro and in vivo by down-regulating the expression of a number of cellular genes involved in cell proliferation and apoptosis...
  26. ncbi Tumor suppressor LKB1 inhibits activation of signal transducer and activator of transcription 3 (STAT3) by thyroid oncogenic tyrosine kinase rearranged in transformation (RET)/papillary thyroid carcinoma (PTC)
    Dong Wook Kim
    Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine, Department of Pathology, Chungnam National University School of Medicine, Daejeon 301 721, Korea
    Mol Endocrinol 21:3039-49. 2007
    ..Thus, this study suggests that LKB1 suppresses tumor growth by inhibiting RET/PTC-dependent activation of oncogenic STAT3...
  27. pmc Tumor suppressive protein gene associated with retinoid-interferon-induced mortality (GRIM)-19 inhibits src-induced oncogenic transformation at multiple levels
    Sudhakar Kalakonda
    Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, 660 West Redwood St, Howard Hall 350, Baltimore, MD 21201, USA
    Am J Pathol 171:1352-68. 2007
    ..Thus, GRIM-19 not only blocks src-induced gene expression through STAT3 but also the activation of cell adhesion molecules...
  28. pmc The interferon signaling network and transcription factor C/EBP-beta
    Hui Li
    Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, 660 W Redwood Street, Baltimore, MD 21201, USA
    Cell Mol Immunol 4:407-18. 2007
    ..Here we describe the non-STAT pathways that participate in IFN-induced responses. In particular, we will focus on the role played by transcription factor C/EBP-beta in mediating these responses...
  29. ncbi Effects of plasmid-based Stat3-specific short hairpin RNA and GRIM-19 on PC-3M tumor cell growth
    Ling Zhang
    Prostate Diseases Prevention and Treatment Research Center and Department of Pathophysiology, School of Basic Medicine, Jilin University, Changchun, PR China
    Clin Cancer Res 14:559-68. 2008
    ..To enhance the therapeutic efficacy of Stat3-specific shRNA, we applied a combination treatment involving gene associated with retinoid-IFN-induced mortality 19 (GRIM-19), another inhibitor of STAT3, along with shRNA...
  30. pmc Critical role for transcription factor C/EBP-beta in regulating the expression of death-associated protein kinase 1
    Padmaja Gade
    Department of Microbiology and Immunology, University of Maryland School of Medicine, 660 West Redwood St, Howard Hall 350, Baltimore, MD 21201, USA
    Mol Cell Biol 28:2528-48. 2008
    ..Together, our data show a critical role for C/EBP-beta in a novel IFN-induced cell growth-suppressive pathway via DAPK1...
  31. pmc Role of the translational repressor 4E-BP1 in the regulation of p21(Waf1/Cip1) expression by retinoids
    Padma Kannan-Thulasiraman
    Robert H Lurie Comprehensive Cancer Center and Division of Hematology Oncology, Northwestern University Medical School and Jesse Brown VA Medical Center, 303 East Superior, Chicago, IL, USA
    Biochem Biophys Res Commun 368:983-9. 2008
    ..Altogether, these findings strongly suggest a key regulatory role for the translational repressor 4E-BP1 in the generation of retinoid-dependent functional responses...
  32. pmc A Fra-1-dependent, matrix metalloproteinase driven EGFR activation promotes human lung epithelial cell motility and invasion
    Pavan Adiseshaiah
    Department of Environmental Health Sciences, Bloomberg School of Public Health, Baltimore, Maryland, USA
    J Cell Physiol 216:405-12. 2008
    ..Taken together, our data suggest that Fra-1 enhances lung cancer epithelial cell motility and invasion by inducing the activity of MMPs, in particular MMP-2 and MMP-9, and EGFR-activated signaling...
  33. pmc The Med1 subunit of transcriptional mediator plays a central role in regulating CCAAT/enhancer-binding protein-beta-driven transcription in response to interferon-gamma
    Hui Li
    Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    J Biol Chem 283:13077-86. 2008
    ..Last, an ERK-regulated site in Med1 protein is also essential for up-regulating IFN-induced transcription although not critical for binding to C/EBP-beta...
  34. pmc ERK signaling regulates tumor promoter induced c-Jun recruitment at the Fra-1 promoter
    Pavan Adiseshaiah
    Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Room E7610, 615 North Wolfe Street, Baltimore, MD 21205, USA
    Biochem Biophys Res Commun 371:304-8. 2008
    ..Inhibition of ERK1/2 pathway suppresses Elk1 activation, and c-Jun and Fra-2 recruitment to the promoter...
  35. pmc IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain
    Fang Shen
    Department of Oral Biology, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
    Sci Signal 2:ra8. 2009
    ..This detailed dissection is the first for the IL-17-mediated C/EBP pathway and the first known example of a negative signal mediated by IL-17RA...
  36. ncbi E2F1 Induces tumor cell survival via nuclear factor-kappaB-dependent induction of EGR1 transcription in prostate cancer cells
    Chaogu Zheng
    Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, Peoples Republic of China
    Cancer Res 69:2324-31. 2009
    ..Together, these studies uncovered a novel mechanism for E2F1-induced suppression of apoptosis in prostate cancer. [Cancer Res 2009;69(6):2324-31]...
  37. pmc The NRF2 activation and antioxidative response are not impaired overall during hyperoxia-induced lung epithelial cell death
    Haranatha R Potteti
    Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
    Oxid Med Cell Longev 2013:798401. 2013
    ..Thus, our findings demonstrate that NRF2 activation and antioxidant gene expression are functional during hyperoxia-induced lung epithelial cell death and that chronic hyperoxia does not impair NRF2 signaling overall...