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Human PAD4 Regulates Histone Arginine Methylation Levels via Demethylimination

Others

Wang et al, 2004. Science, 306:279-283.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=15345777[uid]

*Abstract

Dynamic processes that covalently modify histones play critical roles in regulating gene expression. Misregulation of the "on" and "off" dynamics of histone modifications can lead to diseases such as cancer. Histone acetylation and methylation prevent DNA from coiling tightly, allowing associated genes to be expressed. The opposite processes, deacetylation and demethylation, allow DNA to coil tightly thereby preventing gene expression. While histone deacetylase (HDAC) inhibitors have become important investigative cancer drugs, parallel work to identify demethylase inhibitors has not been able to proceed because the enzymes that remove methyl groups from cellular proteins have been unknown.

 

Researchers from Rockefeller and Weill Cornell are the first to identify a protein with demethylase activity - but with a twist. Their studies demonstrate that human peptidylarginine deaminase 4 (PAD4), which was already known to be able to convert histone arginine to citrulline, can convert a histone's methyl-Arg to citrulline and release methylamine in a process termed demethylimination. PAD4 may be a useful target for drugs to treat cancers that are specifically hormone-responsive because PAD4 is hormonally upregulated and acts on histones associated with hormonally activated genes.

 

Uses

  • Drug discovery: PAD4 may be a target for therapeutics to treat hormone-responsive cancers
  • Diagnostics:
    • Histone methyl-Arg may be useful as a marker of gene activation.
    • Histone citrulline-Arg or free methylamine may be useful as diagnostic markers for PAD activity, gene inactivation, and de-differentiation in cancer.
  • Target discovery: Hormone-induced PAD4 activity can be used to identify genes that are misregulated and turned off in hormone-induced cancers (e.g. breast and prostate), or in developmental disorders.
  • Reagents: The Rockefeller and Cornell labs have recombinant active PAD4; recombinant mutated, inactive PAD4; and several antibodies useful for identifying PAD4, relevant methylated histones, and relevant citrullinated histones.

    • Stage of Development
    Discovery - in vitro studies

*Licensing
Vibhu Sachdev(212) 746-6187sachdev@cornell.edu
Country/Region
USA

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