DNA Binding of the Prostate Homeobox Protein NKX3.1

摘要

NKX3.1 is a homeoprotein with prostate-specific expression in the adult mouse and human. We have identified the hexanucleotide DNA binding domain of NKX3.1. NKX3.1 gene targeting studies in mice have shown that the protein is a differentiating factor and suppress or of epithelial cell growth. We have described a genetic polymorphism, C154T, in humans that alters the amino acid sequence of the protein from arginine to cysteine at amino acid 52 (R52C). This polymorphism is present in 11% of the population. The variant protein has altered phosphorylation of serine 48, adjacent to R52C. The R52C variation results in a 7O% decrease in in vitro phosphorylation of NKX3.1 by protein kinase C. Moreover, whereas DNA binding of wild type protein is regulated by phosphorylation, binding of NKX3.1 R52C to DNA is not affected by phosphorylation. The polymorphic site and an adjacent serine are critical for the activity of the C-terminal inhibitory region of NKX3.l and may mediate binding of C- and N-terminal domains of the protein. Mutations of either R52 to C or S48 to A results in loss of C-terminal region inhibition of transcriptional activation by NKX3.1.