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Occurrence of NKX3.1 C154T Polymorphism in Men with and without Prostate Cancer and Studies of Its Effect on Protein Function¹

Department of Oncology, Lombardi Cancer Center [E. P. G., D. J. S., N. A., H. J. V., M. A., K. S.], and Department of Neurosciences [S. S.], Georgetown University School of Medicine, Washington, DC 20007-2197; Channing Laboratory, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 [J. M., M. J. S.]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892-7354 [R. B. H.]; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115 [M. J. S.]; and Research Center for Genetic Medicine, Children’s National Medical Center, George Washington University Genetics, Washington, DC 20010 [K. M. B.]

NKX3.1, a member of the NK class of homeodomain proteins, is expressed primarilyin the adult prostate and has growth suppression and differentiating effects in prostate epithelial cells. A CT polymorphism at nucleotide 154 (NKX3.1 C154T) is present in 11% of healthy men with equal distribution among whites and blacks. In a cohort of 1253 prostate cancer patients and age-matched controls, the presence of the polymorphism was associated with a 1.8-fold risk of having stage C or D prostate cancer or Gleason score 7 (confidence interval, 1.01–3.22). The NKX3.1 C154T polymorphism codes for a variant protein that contains an arginine-to-cysteine substitution at amino acid 52 (R52C) adjacent to a protein kinase C phosphorylation site at serine 48. Substitution of cysteine for arginine 52 or of alanine for serine 48 (S48A) reduced phosphorylation at serine 48 in vitro and in vivo. Phosphorylation of wild-type NKX3.1, but not of NKX3.1 R52C or NKX3.1 S48A, diminished binding in vitro to a high-affinity DNA binding sequence. NKX3.1 also serves as a transcriptional coactivator of serum response factor. Treatment of cells with 12-O-tetradecanoylphorbol-13-acetate to phosphorylate NKX3.1 had no effect on NKX3.1 coactivation of serum response factor. Neither the R52C nor the S48A substitution affected serum response factor coactivation by NKX3.1 We conclude that the polymorphic NKX3.1 allele codes for a variant protein with altered DNA binding activity that may affect prostate cancer risk.

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