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Charles R. Vinson, Ph.D.
Gene Regulation and Function: The bZIP Proteins
The regulation of gene expression underlies all cellular processes, including cancer. We are developing new gene-based protein methods to regulate genes, including (1) dominant-negatives (DNs) that inhibit the DNA binding of endogenous transcription factors, resulting in modulation of gene expression, and (2) gain-of-function genes that bind new DNA sequences, resulting in new gene expression.
We have developed dominant-negatives to the dimeric B-ZIP (CREB, PAR, AP-1, and C/EBP) and B-HLH-ZIP (USF, Myc, and Mi) transcription factors. These dominant-negatives contain the dimerization domain of the transcription factor and an acidic protein sequence that replaces the basic region. The dominant-negatives heterodimerize with the endogenous transcription factors and prevent DNA binding.
We are studying in detail the structural rules that regulate leucine zipper dimerization specificity and sequence-specific DNA binding. Our recent work suggests that intracellular regulation of magnesium has profound effects on the sequence-specific DNA binding of B-ZIP proteins and highlights the possibility that magnesium may be an intracellular second messenger, similar to its larger cousin, calcium.
We have expressed a dominant-negative that inhibits both the C/EBP and JUN family of transcription factors in fat tissue. The resulting mouse is ?fatless? and has severe diabetes. Using the new microarray technology, we are characterizing the genes that are misregulated. We are starting a project to examine the blood serum from these mice to identify missing peptides as possible hormones secreted from fat. This could have profound implications for the regulation of energy homeostasis.
We are expressing these DNs in an inducible manner in transgenic mice to generate new phenotypes and identify transcriptional targets. Preliminary results obtained in collaboration with others indicate that expression of a dominant-negative to Jun (A-Fos) inhibits tumor formation.
We have also placed these DNs into adenoviral vectors. We have shown that expression of A-Fos potentiates killing of the chemotherapeutic resistant cell lines. We are extending these studies to determine if expression of A-Fos selectively kills cancer cells.
This page was last updated on 2/26/2013.