Dr. Anil Kumar Jaiswal was born in India. He received his Ph.D. in Biochemistry from the University of Lucknow, Lucknow, India. He did his Post-Doctoral Training from National Institutes of Health, Bethesda, Maryland (1983-1987). He joined as Assistant Professor at NYU Medical Center, New York followed by Associate Member in Fox Chase Cancer Center, Philadelphia. He moved to Baylor College of Medicine Houston, TX as Associate Professor in 1997 and was promoted to Full Professor in 2004. He joined the Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore, Maryland as Full Professor in 2007. He served on numerous NIH CSR review panels for grants, center grants and cancer centers. He also served on Editorial boards and was invited to present his work in numerous national and international forums.
Our research interests include: oxidative stress signaling with a focus on Nrf2:INrf2 (Keap1) signaling; cell survival and death; chemoprevention; oncogenesis with focus on hematological malignancies, skin, breast and prostate cancer, and metastasis; drug resistance; and bioreductive drug development.
Oxidative Stress: Nrf2:INrf2 (Keap1) Signaling in Cell Survival and Death:
Oxidative stress is associated with degenerative diseases, apoptotic cell death, aging, cellular transformation and cancer. 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 one hundred cytoprotective genes including biotransformation/detoxifying enzymes, transporters, and anti-apoptotic proteins that protect against oxidative stress and neoplasia, in order to promote cell survival (Fig. 1). Our lab has focused on Nrf2 and its role in oxidative stress. We have identified antioxidant response element (ARE) and NF-E2 related transcription factors (Nrf2, Nrf1 and Nrf3) that regulate the expression and coordinated induction of cytoprotective genes in response to oxidants, antioxidants, xenobiotics, and radiation. Included in this battery of gene products are antioxidant enzymes [quinone oxidoreductases (NQO1 and NQO2)], antioxidants, anti-apoptotic factors, and tumor suppressor p53. Furthermore, we have determined that Nrf2 is retained in the cytoplasm by a repressor protein INrf2 (Keap1). INrf2 has been cloned and sequenced. The studies also suggested that the INrf2:Nrf2 complex serves as a sensor of chemical/radiation-induced oxidative stress. We 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 cytoprotective genes. Currently, we are utilizing molecular biological and biochemical techniques to identify and study the role of the various regulatory molecules that include serine/threonine and tyrosine kinases (PKCs, PI3K/Akt, GSK3¿, and Src kinases); phosphatases (PTEN, PP1 and PP2); and redox proteins (NADPH Oxidases, Thioredoxin and Thioredoxin Reductase) in transduction of a signal from ROS to the Nrf2/ARE, which then regulates the induction of a battery of cytoprotective genes leading to cytoprotection and cell survival. The studies are also being performed to determine the role of Nrf2:INrf2 signaling/regulatory molecules/pathways in cell survival and apoptotic cell death.
Mouse Models of Cancer:
Global knockout and Flox/Cre mouse models have been, and are currently being, generated in our laboratory to study the in vivo role of Nrf2, INrf2(Keap1), NQO1 and NQO2 proteins in different cancers.
Primary and Therapy-Related Leukemia and lymphoma:
Disruption of NQO1 and NQO2 in mice led to myelogenous hyperplasia and γ-radiation induced myeloproliferative diseases including myeloid leukemia and B-cell lymphoma. In addition, a significant percentage of human individuals with primary and chemotherapy-induced secondary leukemia carry both mutant NQO1 P187S alleles and are deficient in NQO1 protein. These studies together suggest that NQO1 and NQO2 are endogenous factors in protection against primary and therapy-related leukemia and lymphoma. Current goals are to investigate the in vivo role of NQO1 and NQO2 in benzene and chemotherapy-related leukemia/lymphoma. The studies are also investigating the mechanism of the role of NQO1 and NQO2 in protection of myeloid differentiation factors C/EBPa and Pu.1, tumor suppressor p53 and other growth/differentiation factors against 20S proteasomal degradation leading to protection against leukemia and lymphoma.
NQO1-null and NQO2-null mice both show increased susceptibility to chemical-induced skin tumors indicating a role of these proteins in skin cancer prevention. Current studies are focused on in vivo role of Nrf2, INrf2, NQO1 and NQO2 in UVB-induced skin cancer. We are also studying the role of NQO1 and NQO2 in stabilization of tumor suppressor p53 and epithelial cell differentiation factor p63 against 20S proteasomal degradation and its significance in protection against chemical induced skin carcinogenesis. In addition, we are performing microarray and proteomic analyses to identify the growth/proliferation/differentiation genes/proteins that might also be the targets leading to increased sensitivity to chemically-induced skin cancer in NQO1-null and NQO2-null mice.
Breast and Prostate Cancer:
Preliminary studies have suggested a role of Nrf2 and NQO1 in breast and prostate cancer prevention. Current studies are investigating in vivo role of Nrf2, INrf2, NQO1 and NQO2 in breast and prostate cancer susceptibility and metastasis. We are also investigating the mechanism of the role of Nrf2 and downstream proteins in cancer prevention.
Mouse Models of Asthma and COPD:
A role of Nrf2 has been shown in protection against COPD. We are using lung specific mouse models of Nrf2 and INrf2 and global NQO1-null and NQO2-null mice to determine in vivo role of Nrf2, INrf2, NQO1 and NQO2 in protection against Asthma and COPD. Studies are also being performed to determine the mechanism of protection.
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 was found overexpressed in many tumors that qualify these tumors for selective activation of drugs. 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.
Nrf2:INrf2 and Chemotherapeutic Drug Resistance:
Aromatase inhibitors (AI) are excellent chemotherapeutic drugs to treat breast cancer. However, drug resistance is often a problem. We have observed overexpression of Nrf2 and anti-apoptotic proteins in AI resistance. Current studies are investigating the role of Nrf2 and associated factors in AI resistance and developing therapies to combat AI resistance.
Lab Techniques and Equipment:
Protein biochemistry, protein trafficking, molecular biology, signaling, kinases and redox factor studies, cancer biology, apoptosis, imaging, knockout mice, conditional knockout mice, humanized mice, microarray, proteomics, mass spectra analysis of protein modifications including phosphorylation, glycosylation, and ubiquitination, siRNA, shRNA, flow cytometry, cancer models, asthma and COPD models, histology, immunohistochemistry.