Anil K. Jaiswal, Ph.D.

Professor
Department of Pharmacology

Ph.D., University of Lucknow, (1980) India
Postdoctoral, National Institutes of Health, Bethesda

OXIDATIVE STRESS AND REGULATION OF GENE EXPRESSION

Our research interests include ‘Oxidative Stress Signaling, Oncogenesis, Chemoprevention and Bioreductive Drug Activation and Drug development'. Oxidative stress is associated with degenerative diseases of hepatic, renal, cardiovascular and nervous tissues, apoptotic cell death, aging, cellular transformation and neoplasia. The initial response of cells to oxidative stress is to turn on signal(s) that lead to the coordinated activation of a battery of more than five dozen defensive genes that protect against oxidative stress and neoplasia. Included in this battery of gene products are antioxidant enzymes [quinone oxidoreductases (NQO1 and NQO2)], antioxidants, and tumor suppressor p53. We have identified antioxidant response element (ARE) and NF-E2 related transcription factors (Nrf1, Nrf2 and Nrf3) that regulate expression and induction of defensive genes in response to oxidants, antioxidants and xenobiotics. We further determined that Nrf2 is retained in the cytoplasm by a repressor protein called INrf2. INrf2 has been cloned and sequenced in our laboratory. Preliminary studies have identified kinase(s) and redox factors that mediate signal transduction from ROS to the cytosolic Nrf2/INrf2 complex leading to the release of Nrf2 from INrf2, nuclear localization of Nrf2 and coordinated activation of ARE-containing defensive genes. Currently, we are utilizing molecular biological and biochemical techniques to identify and study the role of the various regulatory molecules in transduction of a signal from ROS to the ARE, which then regulates the induction of a battery of defensive genes.

Knockout mouse models have been, and are being, generated in our laboratory to study the in vivo role of proteins responsive to oxidative stress in cancer. We have generated knockout mice that do not express NQO1 and NQO2. Both NQO1-null and NQO2-null mice have myelogenous hyperplasia in the bone marrow and show increased susceptibility to chemical-induced skin tumors. We are testing whether NQO1-null and NQO2-null mice demonstrate an increased susceptibility to developing myeloid leukemia. In addition, we are performing microarray and proteomic analyses to identify the growth/proliferation/differentiation genes/proteins that might be the targets leading to myelogenous hyperplasia of bone marrow, myeloid leukemia and increased sensitivity to chemically-induced skin cancer in NQO1-null and NQO2-null mice.

Bioreductive chemotherapy is based on reductive activation of drugs by enzymes, identification of tumors rich in those enzymes, and differences in oxygen and pH between normal and tumor tissues. Recently, we have identified and cloned the cytosolic glucose regulatory protein (GRP58) that plays a significant role in activation of antitumor drug mitomycin C leading to DNA cross-linking and cell death. GRP58 found overexpressed in many tumors qualifies for selective activation of drugs in tumors. Recent studies have also shown that significant percentage of human individuals with chemotherapy-induced secondary leukemia carry both mutant NQO1 P187S alleles and are deficient in NQO1 protein. However, it is unknown if the absence of NQO1 contributed to chemotherapy-induced leukemia. Our current goals are to determine the mechanism of the role of GRP58 in mitomycin C-induced DNA cross-linking and study the in vivo role of GRP58 in mouse development and anti-tumor drug toxicity. In addition, investigate the in vivo role of NQO1 in chemotherapy-related secondary leukemia.

In addition, we are generating single and double knock out mice that do not express one or more of the detoxifying enzymes to study their role in chemical induced oxidative stress, cellular transformation and cancer.

Selected Publications:

V. Radjendirane and Anil K. Jaiswal. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc. Natl. Acad. Sci. USA , 93: 14960-14965, (1996).

V. Radjendirane, P. Joseph and Anil K. Jaiswal. Gene expression of DT-diaphorase (NQO1) in cancer cells. In "Oxidative Stress and Signal Transduction". Edited by Henry J. Forman and Enrique Cadenas. Publisher Chapman & Hall, New York. pp441-475 (1997).

Anil K. Jaiswal, A. Carothers and D. Grunberger. Caffeic acid phenethyl ester (CAPE) stimulates hARE-mediated CAT gene expression. Cancer Research, 57: 440-446 (1997).

Kebin Wu, Richard Knox, Xiu Zhu Sun, Pius Joseph, Anil K. Jaiswal, Di Zhang, Paulis S.-K. Deng and Shiuan Chen. Catalytic Properties of NAD(P)H:Quinone Oxidoreductase-2 (NQO2), a Dihydronicotinamide Riboside dependent oxidoreductase. Arch. Biochem. Biophys. 347: 221-228 (1997)

Pius. Joseph and Anil K. Jaiswal. NAD(P)H: quinone oxidoreductase1 (NQO1) reduces the mutagenicity of DNA caused by NAD(P)H:P450 reductase activated metabolites of benzo(a)pyrene quinones. British J. Cancer 77: 709-719, (1998)

Pius. Joseph, A.J.P. Klein-Szanto and Anil K. Jaiswal. Hydroquinones cause specific frame shift mutations involving deletion of a single cytosine from the DNA sequence 5'-CCCCC-3' and lead to cellular transformation and in vivo tumorigenesis. British J. Cancer 78:312-320 (1998).

Venugopal. Radjendirane, Pius. Joseph, Ying-Hue Lee, Shioko Kimura, Andres J.P. Klein-Sazanto, Frank J. Gonzalez and Anil K. Jaiswal. Disruption of the DT Diaphorase (NQO1) in mice leads to increased menadione toxicity. J. Biol. Chem. 273: 7382-7389, (1998).

Saravanakumar Dhakshinamoorthy and Anil K. Jaiswal. Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene 20: 3906-3917, 2001.

Amos Gaikwad, Delwin J. LongII, Janet L. Stringer and Anil K. Jaiswal. In vivo role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the regulation of intracellular redox state and accumulation of abdominal adipose tissue. J. Biol. Chem. 276: 22559-22564, 2001.

Delwin J. LongII, Rebekah L. Waikel, Xiao-Jing Wang, Dennis R. Roop and Anil K. Jaiswal. NAD(P)H:quinone oxidoreductase1 (NQO1) deficiency increases susceptibility to 7, 12-Dimethylbenz[a]anthracene induced mouse skin carcinogenesis. J. Natl. Cancer Inst. 93: 1166-1170, 2001.

David. Bloom, Saravanakumar Dhakshinamoorthy, Wei. Wang, Claudia M. Celli and Anil K. Jaiswal. Role of NF-E2 related factors in oxidative stress. Cell and Molecular Responses to Stress 2: 229-238 (2001).

Amos Gaikwad, Saravanakumar Dhakshinamoorthy, David Bloom and Anil K. Jaiswal. Antioxidant induction of genes encoding detoxifying enzymes. Cell. Mol. Toxicol. 14: 377-387 (2002).

David Bloom, Saravanakumar Dhakshinamoorthy and Anil K. Jaiswal. Site-directed mutagenesis of cysteine to serine in the DNA binding region of Nrf2 decreases its capacity to upregulate antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene 28: 2191-2200 (2002).

Delvin J. Long II, Amos Gaikwad, Asha Multani, Sen Pathak, Charles A. Montgomery, Frank J. Gonzalez, and Anil K. Jaiswal. Disruption of the NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Gene in Mice Causes Myelogenous Hyperplasia. Cancer Res. 62: 3030-3036 (2002).

Saravanakumar Dhakshinamoorthy and A. K. Jaiswal. c-Maf negatively regulates ARE-mediated detoxifying enzyme genes expression and anti-oxidant induction. Oncogene 21: 5301-5312 (2002).

LongII, K. Iskander, A. Gaikwad, M. Arin, D. R. Roop, R. Knox, R. Barrios and A. K. Jaiswal. Disruption of dihydronicotinamide riboside:quinone oxidoreductase2 (NQO2) leads to myeloid hyperplasia of bone marrow and decreased sensitivity to menadione toxicity. J. Biol. Chem. 277: 46131-46139, 2002.

C. M. Celli, and A. K. Jaiswal. Role of GRP58 in mitomycin C-induced DNA cross-linking. Cancer Research 63: 6016-6025, 2003.

A. Bloom, and A. K. Jaiswal Phosphorylation of Nrf2S40 by PKC in response to antioxidants leads to the release of Nrf2 from Inrf2 but not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of ARE-mediated NQO1 gene expression. J. Biol. Chem. 278: 44675-44682, 2003.

K. Iskander, M. Paquet, C. Brayton, and A. K. Jaiswal. Deficiency of NRH:quinone oxidoreductase 2 (NQO2) increases susceptibility to 7,12-dimethylbenz[a]anthracene and benzo(a)pyrene-induced skin carcinogenesis. Cancer Research 64: 5925-5928, 2004.

Phone: (713) 798-7691

FAX: (713) 798-3145

e-mail: ajaiswal@bcm.tmc.edu