Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Role of Z-DNA forming silencer in the regulation of human ADAM-12 gene expression
ADAM-12 is a member of novel multifunctional ADAM family of proteins. Expression of ADAM-12 is upregulated in many human cancers, arthritis and cardiac hypertrophy. The multidomain structure composed of a prodomain, a metalloproteinase, disintegrin-like, epidermal growth factor-like, cysteine-rich and transmembrane domains and a cytoplasmic tail allows ADAM-12 to promote matrix degradation, cell-cell adhesion and intracellular signaling capacities (1). Basal expression of ADAM-12 is very low in adult tissues but rises markedly in response to certain physiological cues, such as during pregnancy in the placenta, during development in neonatal skeletal muscle and bone and in regenerating muscle (2,3). We have identified a highly conserved negative regulatory element (NRE) at the 5′-UTR of human ADAM-12 gene, which acts as a transcriptional repressor (4). The NRE contains a stretch of dinucleotide-repeat sequence that is able to adopt a Z-DNA conformation both in vitro and in vivo. Substitution of the dinucleotide-repeat-element with a non-Z-DNA-forming sequence inhibits NRE function. We have detected Z-DNA-binding protein activity in several tissues where ADAM-12 expression is low while no such activity was seen in the placenta where ADAM-12 expression is high. These observations suggest that interaction of Z-DNA-binding proteins with ADAM-12 NRE is critical for transcriptional repression of ADAM-12. We further show that the Z-DNA forming transcriptional repressor element, by interacting with Z-DNA-binding proteins, is involved in the maintenance of constitutive low-level expression of human ADAM-12. Together these results provide a new insight on the regulatory role of Z-DNA-binding proteins which could be used as therapeutic targets for down-regulation of ADAM-12.
This research has been supported by grants from U.S. Army Medical research and Material Command and University of Missouri.
Department of Veterinary Pathobiology, University of Missouri,
Columbia, MO 65211