Function of parafibromin inhibiting parathyroid tumorigenesis

11个FIHP家系中2个发现HRPT2胚系突变，2个HPT-JT家系中发现1个HRPT2胚系突变。1个伴有甲状旁腺癌和不典型腺瘤的FIHP家系和1个伴有囊性甲状旁腺腺瘤的FIHP家系分别发现了518-521del和62-66del的移码突变。在1例HPT-JT患者中，检测到39delC的新胚系突变。在一个518-521 del突变的家系中，在5个甲状旁腺肿瘤中发现2个新的体细胞HRPT2突变，分别为70-73del和95-102del。在甲状旁腺肿瘤中，通过胚系突变和体细胞突变相结合的方式证实了HRPT2的双等位基因失活。发现两个FIHP家系携带HRPT2突变，提示他们患有隐匿性HPT-JT。副纤维蛋白是由HRPT2编码的531个氨基酸的蛋白质产物，HRPT2是一种可能的肿瘤抑制基因，最近与常染色体显性遗传性甲状旁腺机能亢进症、颌骨肿瘤、家族性癌症综合征和散发性甲状旁腺癌有关。为了研究副纤维蛋白过表达对细胞增殖的影响，我们在四种不同的细胞系中进行了细胞增殖实验。瞬时过表达副纤维蛋白抑制HEK293和NIH3T3细胞的生长，而促进表达SV40大T抗原的293FT和COS7细胞的生长。在293FT细胞中，副纤维蛋白与SV40大T抗原相互作用，过表达的副纤维蛋白促进细胞进入S期，提示副纤维蛋白与SV40大T抗原的相互作用促进了细胞周期的进展。基于这些，我们得出结论，肿瘤抑制蛋白，副纤维蛋白，在SV40大T抗原存在的情况下，对细胞生长起到积极的调节作用，如癌蛋白。

Germline mutations of HRPT2 were found in 2 of 11 FIHP families and 1 of 2 HPT-JT families. One FIHP family with parathyroid carcinoma and atypical adenomas, and another FIHP family with cystic parathyroid adenoma had novel frameshift mutations of 518-521del and 62-66del, respectively. In a patient with HPT-JT, a de novo germline mutation of 39delC was detected. Novel somatic HRPT2 mutations of 70-73del and 95-102del were found in 2 of 5 parathyroid tumors in a family with 518-521 del mutation. Biallelic inactivation of HRPT2 by a combination of germline mutation and somatic mutation was confirmed in parathyroid tumors. The finding that 2 families diagnosed with FIHP carried HRPT2 mutations suggests that they have occult HPT-JT.Parafibromin is a 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 and sporadic parathyroid carcinoma. To investigate effects of parafibromin overexpression on cell proliferation, we performed cell proliferation assay in four different cell lines. Transient parafibromin overexpression inhibited cell growth in HEK293 and NIH3T3 cells, whereas enhanced cell growth in SV40 large T antigen expressing-cell lines such as 293FT and COS7 cells. In 293FT cells, the parafibromin was found to interact with SV40 large T antigen and overexpression of parafibromin promoted entry into S phase, implying that interaction between parafibromin and SV40 large T antigen enhanced cell cycle progression. Based on these we conclude that tumor suppressor protein, parafibromin, acts a positive regulator of cell growth such as oncoproteins at the presence of SV40 large T antigen.