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Charles R. Vinson, Ph.D.

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A-ZIP Proteins
A-ZIP Proteins
My lab studies the structure-function relationships of the mammalian B-ZIP class of sequence-specific DNA binding dimeric proteins. More than 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 are studying B-ZIP transcriptional function using dominant-negatives (DNs) we have designed 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-ZIPs.
A-Zip
A-Zip
The utility of these reagents to alter living systems was examined by producing transgenic mice expressing an A-ZIP dominant negative in only fat cells. The transgenic mice have 20 copies of a construct consisting of 7.6 kb of the fat specific aP2 promoter driving expression of an A-ZIP dominant negative that inhibits the DNA binding of both CEBP and FOS/JUN B-ZIP domains. The resultant mouse has essentially no fat. The metabolic consequences are profound, mimicking the human disease lipodystrophy. The mouse eats 1.7 fold more food and the liver is 2.3 fold larger than normal. The diabetic nature of the metabolic confusion is seen in insulin levels that are 100 fold higher than normal and glucose levels that are 3 fold elevated. The mice die prematurely, starting at 5 months. Troglitazone, a thiazolidinedione agonist of the transcription factor PPRg, reverses the diabetes.

This page was last updated on 11/15/2010.