My laboratory studies the structure-function relationships of the B-ZIP class of sequence-specific DNA binding dimeric proteins. Over 50 B-ZIP genes have been identified in the mammalian genome. In the most general terms, B-ZIP proteins both activate and repress gene expression in response to physiological changes, be it growth factors (FOS), stress (ATF2), neuronal signaling (CREB), or metabolic changes (CEBP). We want to study B-ZIP transcriptional function using dominant-negatives (DN's) that inhibit B-ZIP DNA binding. A problem with the design of such reagents is that B-ZIP proteins become stabilized by binding DNA. We have overcome this problem by extending the dimerization domain into the basic region to produce A-ZIP's. The A represents an N-terminal Acidic amphipathic extension of the leucine zipper that replaces the basic region critical for sequence-specific DNA binding of the B-ZIP dimer. These A-ZIP proteins act as D-N's by inhibiting the DNA binding of B-ZIP proteins because of the stabilization that occurs through the interaction of the acidic extension with the basic region of the B-ZIP domain. They form an alpha-helical coiled coil extension of the leucine zipper. The pathology of excited stress pathways caused by B-ZIP proteins can be examined using these A-ZIPs. Ultimately, we hope to use these gene-based A-ZIPs as adjuvants with other medical approaches to cure human disease, particularly chemotherapy resistant cancers. The hypothesis driving this work is that direct transcriptional targets of a B-ZIP protein can be identified by expression of the corresponding A- ZIP protein.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005271-06
Application #
6160888
Study Section
Special Emphasis Panel (LB)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Golla, Jaya Prakash; Zhao, Jianfei; Mann, Ishminder K et al. (2014) Carboxylation of cytosine (5caC) in the CG dinucleotide in the E-box motif (CGCAG|GTG) increases binding of the Tcf3|Ascl1 helix-loop-helix heterodimer 10-fold. Biochem Biophys Res Commun 449:248-55
Vinson, Charles; Chatterjee, Raghunath (2012) CG methylation. Epigenomics 4:655-63
Chatterjee, Raghunath; Vinson, Charles (2012) CpG methylation recruits sequence specific transcription factors essential for tissue specific gene expression. Biochim Biophys Acta 1819:763-70
Yuan, Zhongmin; Gong, Shoufang; Luo, Jingyan et al. (2009) Opposing roles for ATF2 and c-Fos in c-Jun-mediated neuronal apoptosis. Mol Cell Biol 29:2431-42
Rozenberg, Julian; Rishi, Vikas; Orosz, Andras et al. (2009) Inhibition of CREB function in mouse epidermis reduces papilloma formation. Mol Cancer Res 7:654-64
Oh, Won Jun; Rishi, Vikas; Orosz, Andras et al. (2007) Inhibition of CCAAT/enhancer binding protein family DNA binding in mouse epidermis prevents and regresses papillomas. Cancer Res 67:1867-76
Oh, Won-Jun; Rishi, Vikas; Pelech, Steven et al. (2007) Histological and proteomic analysis of reversible H-RasV12G expression in transgenic mouse skin. Carcinogenesis 28:2244-52
Nunez, Nomeli P; Oh, Won-Jun; Rozenberg, Julian et al. (2006) Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation. Cancer Res 66:5469-76
FitzGerald, Peter C; Sturgill, David; Shyakhtenko, Andrey et al. (2006) Comparative genomics of Drosophila and human core promoters. Genome Biol 7:R53
Acharya, Asha; Rishi, Vikas; Moll, Jonathan et al. (2006) Experimental identification of homodimerizing B-ZIP families in Homo sapiens. J Struct Biol 155:130-9

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