NAD (P)H:quinone oxidoreductase1 (NQO1) and NRH:quinone oxidoreductase2 (NQO2) are enzymes that generally detoxify quinones, and protect against oxidative stress. NQO1-/-, NQO2-/-, and double knockout (DKO) mice were generated in our laboratory. All were born normal, however, NQO1-/- mice exhibited painful bladder syndrome (PBS). Microarray analysis of bladders from wild type and NQO1-/- mice revealed that PPAR?C1a /MUP1/MUP2 factors regulating mitochondrial biogenesis, energy metabolism and adhesion were down regulated in NQO1-/- mice. However, the mechanism by which NQO1 controls these factors remains unknown. Epidemiological studies have shown an association between human NQO1P187S mutation and cigarette smoke related bladder cancer. This suggests a role of NQO1 and possibly NQO2 in cigarette smoke- induced bladder cancer that remains to be elucidated. DKO mice showed hyperoxic lung injury/infiltration with neutrophils. This together with epidemiological reports of association between NQO1P187S mutation and asthma raise intriguing questions regarding the role of NQO1/NQO2 in cigarette smoke-induced pulmonary emphysema. NQO1-/-, NQO2-/- and DKO mice demonstrated significantly higher susceptibility to develop skin tumors in response to benzo(a)pyrene and DMBA, as compared with wild type mice. Further studies revealed that NQO1 and NQO2 stabilization of tumor suppressor p53 against 20S proteasome degradation and down regulation of p63 and MAPK pathway contributed to carcinogenesis. However, a complete mechanism remains unknown and warrants further investigation. Studies have suggested that stress-inducible NQO1 and NQO2 regulation of key factors in different tissues against 20S degradation might be one major mechanism of protection and survival against endogenous and environmental stressors and requires investigation. The proposed studies will investigate the central hypothesis that NQO1 and NQO2 control key tissue factors/pathways that leads to protection against PBS and cigarette smoke-induced bladder cancer and lung emphysema. The studies will also determine the in-depth mechanism of NQO1 and NQO2 control of factors.
Three aims are proposed.
Aim 1 will determine if NQO1 mice demonstrate PBS and test the hypothesis that the loss of NQO1 alters key factors in control of mitochondrial biogenesis, energy metabolism, membrane integrity, and additional yet unidentified pathways that leads to PBS. In addition, investigate the susceptibility of NQO1 and NQO2 deficient mice to cigarette smoke-induced bladder cancer.
Aim 2 will investigate in vivo role of NQO1 and NQO2 in cigarette smoke-induced lung emphysema. In addition, identify NQO1/NQO2 control of factors in protection against lung emphysema.
Aim 3 will study in-depth mechanism by investigating the central hypothesis that NQO1 and NQO2 regulation of key factors against degradation by 20S proteasomes leads to protection against chemical carcinogenesis and PBS. The studies are clinically relevant since a significant number of individuals are deficient in NQO1 and NQO2, or both due to mutations/gene alterations.

Public Health Relevance

NAD(P)H:quinone oxidoreductase1 (NQO1) and NRH:quinone oxidoreductase2 (NQO2) are cytosolic proteins that play significant role in prevention of xenobiotic and nutrient-induced redox cycling and oxidative stress. Preliminary data presented demonstrate that NQO1 and NQO2 might play significant roles in protection against chemical/radiation induced tissue specific diseases and cancer. The proposed studies are focused to investigate the in vivo role of NQO1 and NQO2 in the control of key tissue factors/pathways leading to protection against painful bladder syndrome and cigarette smoke-induced bladder cancer and pulmonary emphysema. The studies are clinically relevant since significant numbers of individuals are deficient in NQO1 or NQO2 or both due to mutations and gene alterations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES007943-17
Application #
8438269
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Thompson, Claudia L
Project Start
1996-08-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
17
Fiscal Year
2013
Total Cost
$330,750
Indirect Cost
$110,250
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Xu, Junkang; Patrick, Brad Allen; Jaiswal, Anil K (2013) NRH:quinone oxidoreductase 2 (NQO2) protein competes with the 20 S proteasome to stabilize transcription factor CCAAT enhancer-binding protein ? (C/EBP?), leading to protection against ? radiation-induced myeloproliferative disease. J Biol Chem 288:34799-808
Patrick, B A; Gong, X; Jaiswal, A K (2011) Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to 20S proteasomal degradation of p63 resulting in thinning of epithelium and chemical-induced skin cancer. Oncogene 30:1098-107
Shen, Jun; Barrios, Roberto J; Jaiswal, Anil K (2010) Inactivation of the quinone oxidoreductases NQO1 and NQO2 strongly elevates the incidence and multiplicity of chemically induced skin tumors. Cancer Res 70:1006-14
Iskander, Karim; Barrios, Roberto J; Jaiswal, Anil K (2009) NRH:quinone oxidoreductase 2-deficient mice are highly susceptible to radiation-induced B-cell lymphomas. Clin Cancer Res 15:1534-42
Voynow, Judith A; Fischer, Bernard M; Zheng, Shuo et al. (2009) NAD(P)H quinone oxidoreductase 1 is essential for ozone-induced oxidative stress in mice and humans. Am J Respir Cell Mol Biol 41:107-13
Iskander, Karim; Barrios, Roberto J; Jaiswal, Anil K (2008) Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to radiation-induced myeloproliferative disease. Cancer Res 68:7915-22
Gong, Xing; Gutala, Ramana; Jaiswal, Anil K (2008) Quinone oxidoreductases and vitamin K metabolism. Vitam Horm 78:85-101
Wang, Wei; Le, Wei-Dong; Pan, Tianhong et al. (2008) Association of NRH:quinone oxidoreductase 2 gene promoter polymorphism with higher gene expression and increased susceptibility to Parkinson's disease. J Gerontol A Biol Sci Med Sci 63:127-34
Kondraganti, Sudha R; Jiang, Weiwu; Jaiswal, Anil K et al. (2008) Persistent induction of hepatic and pulmonary phase II enzymes by 3-methylcholanthrene in rats. Toxicol Sci 102:337-44
Ahn, Kwang Seok; Gong, Xing; Sethi, Gautam et al. (2007) Deficiency of NRH:quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes: up-regulation of apoptosis correlates with down-regulation of cell survival kinases. Cancer Res 67:10004-11

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