title: Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression.
abstract: Parafibromin is the 531-amino-acid protein product encoded by HRPT2, a putative tumor suppressor gene recently implicated in the autosomal dominant hyperparathyroidism-jaw tumor familial cancer syndrome, sporadic parathyroid cancer, and a minority of families with isolated hyperparathyroidism. Parafibromin contains no identified functional domains but bears sequence homology to Cdc73p, a budding yeast protein component of the RNA polymerase II-associated Paf1 complex. This study addressed the expression and functional properties of human parafibromin. A survey of human and mouse tissues analysed with polyclonal antibodies to parafibromin showed specific immunoreactivity in adrenal and parathyroid glands, kidney, heart, and skeletal muscle. Subcellular fractionation and laser confocal microscopy of normal human parathyroid gland demonstrated expression of parafibromin in both the cytoplasmic and nuclear compartments. Parafibromin was expressed in four parathyroid adenomas but was absent from two parathyroid carcinomas. Transient overexpression of wild-type parafibromin, but not its Leu64Pro missense mutant implicated in parathyroid cancer and familial isolated hyperparathyroidism, inhibited cell proliferation, and blocked expression of cyclin D1, a key cell cycle regulator previously implicated in parathyroid neoplasia. These results demonstrate that human parafibromin is a nucleocytoplasmic protein with functions consistent with its postulated role as a tumor suppressor protein.
authors.affiliation: 1Metabolic Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Geoffrey E
authors.initials: GE
authors.lastname: Woodard
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhang
authors.forename: Sunita K
authors.initials: SK
authors.lastname: Agarwal
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Marx
authors.forename: William F
authors.initials: WF
authors.lastname: Simonds
mesh_terms: D000236:Adenoma / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism*; D002467:Cell Nucleus / Q000276:immunology; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000096:biosynthesis*; D003593:Cytoplasm / Q000276:immunology; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics; D010280:Parathyroid Glands / Q000276:immunology / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000276:immunology / Q000378:metabolism*; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: C454900:CDC73 protein, human; D011506:Proteins; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1