Interferons (IFN) are a family of multifunctional cytokines that modulate the cellular antitumor, antiviral and immune responses. They are in clinical use for the therapy of human cancers. IFN actions are mediated by IFN stimulated gene (ISG) products. A number of transcription factors are activated though the Janus Kinase-Signal Transducing Activators of Transcription (JAK-STAT) pathway upon stimulation cells with IFNs. Among these is a burgeoning class of transcription factors called the IFN regulatory factors (IRF) which exhibit homology to oncoprotein myb in their DNA binding domains. IRFs are essential for the prevention of leukemia, regulation of apoptosis, cell cycle control and lymphocyte maturation. P48, an IRF family member, is a DNA binding factor which in association with STAT proteins inhibits tumor growth in IFN-treated cells. IFN-gamma enhances biological responses to IFN-alpha/beta through an increase in p48 gene expression in several cells. In cells transformed by dominant viral oncogenes, IFN responses are inhibited because of repression of p48 gene. The gene encoding p48 is modulated in a unique manner by IFN-gamma because it possesses a novel IFN-gamma response element which does not bind known IFN-regulated factors. Based on our preliminary studies we hypothesize that IFN-gamma modulated expression of p48 is mediated novel factors. We now propose to isolate and characterize the genes encoding these factors and determine their role in cell growth inhibition. Preliminary studies indicate that these factors are distinct but are related to families of regulatory factors involved in cell growth function and prevention of tumor growth. It is likely that mutations in these gene products may contribute to resistance to IFN-therapy. Based on such observations we predict that these factors may be essential not only for regulating IFN-action but also for homeostasis of host defenses. We believe that loss of genes encoding these factors may be linked to human cancers. Thus they may serve as markers for monitoring mutations leading to such diseases. These genes may be useful for genetic therapy of cancer, if such mutated genes are discovered. Therefore, it is important to characterize the actions of these novel factors and their role in growth control.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA078282-01
Application #
2666888
Study Section
Pathology B Study Section (PTHB)
Program Officer
Shen, Grace L
Project Start
1998-09-16
Project End
2003-06-30
Budget Start
1998-09-16
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Gade, Padmaja; Kimball, Amy S; DiNardo, Angela C et al. (2016) Death-associated Protein Kinase-1 Expression and Autophagy in Chronic Lymphocytic Leukemia Are Dependent on Activating Transcription Factor-6 and CCAAT/Enhancer-binding Protein-?. J Biol Chem 291:22030-22042
Nallar, Shreeram C; Kalvakolanu, Dhan V (2014) Interferons, signal transduction pathways, and the central nervous system. J Interferon Cytokine Res 34:559-76
Gade, Padmaja; Manjegowda, Srikanta B; Nallar, Shreeram C et al. (2014) Regulation of the death-associated protein kinase 1 expression and autophagy via ATF6 requires apoptosis signal-regulating kinase 1. Mol Cell Biol 34:4033-48
Udofa, Ekemini A; Stringer, Brett W; Gade, Padmaja et al. (2013) The transcription factor C/EBP-? mediates constitutive and LPS-inducible transcription of murine SerpinB2. PLoS One 8:e57855
Li, Xin; Li, Yang; Wang, Bo et al. (2013) Delivery of the co-expression plasmid pEndo-Si-Stat3 by attenuated Salmonella serovar typhimurium for prostate cancer treatment. J Cancer Res Clin Oncol 139:971-80
Potteti, Haranatha R; Reddy, Narsa M; Hei, Tom K et al. (2013) The NRF2 activation and antioxidative response are not impaired overall during hyperoxia-induced lung epithelial cell death. Oxid Med Cell Longev 2013:798401
Kalvakolanu, Dhananjaya V; Gade, Padmaja (2012) IFNG and autophagy: a critical role for the ER-stress mediator ATF6 in controlling bacterial infections. Autophagy 8:1673-4
Vaz, Michelle; Machireddy, Narsa; Irving, Ashley et al. (2012) Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1. Mol Cell Biol 32:1694-709
Gade, Padmaja; Ramachandran, Girish; Maachani, Uday B et al. (2012) An IFN-?-stimulated ATF6-C/EBP-?-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy. Proc Natl Acad Sci U S A 109:10316-21
Tian, Y; Guo, B; Jia, H et al. (2012) Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC. Cancer Gene Ther 19:393-401

Showing the most recent 10 out of 73 publications