Parafibromin tumor suppressor enhances cell growth in the cells expressing SV40 large T antigen

Abstract

Parafibromin (PF) is a 531-amino acid protein 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 PF's overexpression on cell proliferation, we performed assays in four different cell lines. The transient overexpression of PF inhibited cell growth in HEK293 and NIH3T3 cells, but enhanced cell growth in the SV40 large T antigen-expressing cell lines such as 293FT and COS7 cells. In 293FT cells, PF was found to interact with SV40 large T antigen and its overexpression promoted entry into the S phase, implying that the interaction enhanced progression through the cell cycle. The tumor suppressor protein PF acts as a positive regulator of cell growth similar to an oncoprotein in the presence of SV40 large T antigen.

Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors

“…Parafibromin has been shown by in vitro studies using mammalian cells to have tumor suppressor properties, as its overexpression inhibits the proliferation of NIH3T3 and HEK293 cells [Iwata et al, 2007;Woodard et al, 2005;Zhang et al, 2006], whereas increasing G1 arrest and apoptosis in HeLa cells with a concomitant reduction in S-phase entry [Lin et al, 2007;Zhang et al, 2006]. Parafibromin overexpression also resulted in the downregulation of the cell cycle regulator cyclin D1 [Woodard et al, 2005].…”

“…RNAi-induced inhibition parafibromin expression in Hela cells resulted in increased S-phase entry [Lin et al, 2008;Yart et al, 2005], with a reduction in basal apoptosis [Lin et al, 2007], and an increased expression of the proto-oncogene c-myc [Lin et al, 2008]. Parafibromin has also been reported to act as an oncogene, as its overexpression resulted in the enhanced growth of Cos7 and 293FT cells, which express the SV40 large T antigen [Iwata et al, 2007]. This effect appears to be mediated by a direct interaction between parafibromin and the SV40 large T antigen that results in increased S-phase entry and an enhancement through the cell cycle [Iwata et al, 2007].…”

“…Parafibromin has also been reported to act as an oncogene, as its overexpression resulted in the enhanced growth of Cos7 and 293FT cells, which express the SV40 large T antigen [Iwata et al, 2007]. This effect appears to be mediated by a direct interaction between parafibromin and the SV40 large T antigen that results in increased S-phase entry and an enhancement through the cell cycle [Iwata et al, 2007]. These observations suggest that parafibromin may act as both a tumor suppressor and an oncogene, depending on the cellular environment and the presence or absence of additional factors.…”

Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis

“…In addition, loss of nuclear hCdc73 staining is observed in parathyroid carcinoma 21 . Although mCdc73/HRPT2-deficient mouse embryonic fibroblasts are prone to apoptosis 22 , changes in Cdc73 expression in cell culture exert the reverse effect on cell cycle progression and apoptosis in an SV40 large T-antigendependent manner 23 . These observations suggest that hCdc73 plays a central role in regulating cell growth and cell death.…”

Parathyroid carcinoma

“…Cytoplasmic parafibromin interacts with cytoskeletal proteins [26] and p53 mRNA, modulating p53-mediated apoptosis [27] . Parafibromin can also interact directly with the SV40 large T antigen; cell lines expressing SV40 large T exhibit different effects on proliferation subsequent to perturbation of parafibromin levels [37] , a finding which has complicated interpretation of some in vitro functional analyses.…”