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PURITAN MEDICAL

Blocking BET Family Proteins Prevents Activation of Inflammatory Genes

By BiotechDaily International staff writers
Posted on 12 Mar 2013
A recent paper showed how members of the BET (Bromodomain Extra Terminal) family of dual bromodomain-containing transcriptional regulator proteins directly control the activation of inflammatory genes that contribute to a wide range of diseases from type II diabetes to cancer.

A bromodomain is a protein domain that recognizes acetylated lysine residues such as those on the N-terminal tails of histones. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-alpha protein fold, a bundle of four alpha helices.

Investigators at the Boston University School of Medicine (MA, USA) explored the hypothesis that members of the BET family directly controlled inflammatory genes. They examined the genetic model of brd2 lo mice, a strain with deficient BET proteins, to show that Brd2 was essential for proinflammatory cytokine production in macrophages.

The investigators used two methods to examine the role of Brd2. One was genetic knockdown of Brd2 gene activity with small interfering RNA (siRNA), and the other was by chemical inhibition of BET protein binding with the small molecule JQ1. This protein associates with transcription complexes and with acetylated chromatin during mitosis, and it selectively binds to the acetylated lysine-12 residue of histone H4 via its two bromodomains.

Results published in the February 18, 2013, online edition of the Journal of Immunology revealed that Brd2 and the closely related Brd4 physically associated with the promoters of inflammatory cytokine genes in macrophages. This association was absent in the presence of BET inhibition by JQ1. Furthermore, JQ1 abolished cytokine production in vitro and blunted the “cytokine storm” in endotoxemic mice by reducing levels of interleukin-6 and tumor necrosis factor-alpha while rescuing mice from LPS (lipopolysaccharide)-induced death. Therefore, targeting BET proteins with small-molecule inhibitors may benefit hyperinflammatory conditions associated with high levels of cytokine production.

“Our study suggests that it is not a coincidence that patients with diabetes experience higher risk of death from cancer, or that patients with chronic inflammatory diseases, such as atherosclerosis and insulin resistance, also are more likely to be obese or suffer from inflammatory complications,” said first author Dr. Anna C. Belkina, a researcher in molecular medicine at the Boston University School of Medicine. “This requires us to think of diverse diseases of different organs as much more closely related than our current division of medical specialties allows.”

Related Links:
Boston University School of Medicine



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