Function of parafibromin inhibiting parathyroid tumorigenesis

11个FIHP家族中的2个和2个HPT-JT家族中的1个发现HRPT2种系突变。一个伴有甲状旁腺癌和非典型腺瘤的FIHP家族和另一个伴有囊性甲状旁腺瘤的FIHP家族分别有518-521del和62-66del的新移码突变。在一名HPT-JT患者中，检测到39delC的新生种系突变。在一个518-521 del突变家族的5个甲状旁腺肿瘤中，有2个发现了新的70-73del和95-102del体细胞HRPT2突变。在甲状旁腺肿瘤中证实HRPT2双等位基因失活是由种系突变和体细胞突变联合引起的。发现2个被诊断为FIHP的家庭携带HRPT2突变，表明他们有隐匿的HPT-JT。Parafibromin是一种由HRPT2编码的531个氨基酸的蛋白产物，HRPT2是一种推定的肿瘤抑制基因，最近与常染色体显性甲状旁腺功能亢进症-颌骨肿瘤家族性癌综合征和散发性甲状旁腺癌有关。为了研究parafibromin过表达对细胞增殖的影响，我们对四种不同的细胞系进行了细胞增殖实验。短暂的parafibromin过表达抑制HEK293和NIH3T3细胞的细胞生长，而促进SV40大T抗原表达细胞系如293FT和COS7细胞的细胞生长。在293FT细胞中，发现parafibromin与SV40大T抗原相互作用，parafibromin过表达促进进入S期，这表明parafibromin与SV40大T抗原相互作用促进细胞周期进展。基于这些，我们得出结论，肿瘤抑制蛋白，parafibromin，在SV40大T抗原存在时对细胞生长起积极调节作用，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.