Nuclear Localization of the Parafibromin Tumor Suppressor Protein Implicated in the Hyperparathyroidism-Jaw Tumor Syndrome Enhances Its Proapoptotic Function

Li, Gang; Czapiga, Meggan; Nini, Lylia; Zhang, Jianhua; Simonds, William F.

doi:10.1158/1541-7786.mcr-06-0129

Cited by 66 publications

(63 citation statements)

References 27 publications

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“…Transfection of cells with small interfering duplex RNAs (siRNA) targeting two different sequences of the HRPT2 gene transcript inhibited the expression of endogenous parafibromin in HeLa cells as previously shown ( Fig. 1 A) (10). In addition, treatment of cells with HRPT2-targeted siRNAs also inhibited expression of endogenous Paf1 and Leo1 proteins, both also components of the PAF1 transcriptional regulatory complex, compared to control ( Fig.…”

Section: Resultssupporting

confidence: 73%

“…Anti-proliferative properties are common to many tumor suppressor proteins, as are pro-apoptotic actions such as that recently shown for endogenous parafibromin (10). The c-myc protooncogene has a well-established role in promoting cell proliferation and c-myc transcript levels correlate with the proliferative response of primary cultures of parathyroid cells to serum (27).…”

Section: Discussionmentioning

confidence: 97%

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The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

Zhang²,

Panicker³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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HRPT2 ͉ hyperparathyroidism ͉ parathyroid cancer ͉ PAF1 complex T he tumor suppressor gene HRPT2 was recently identified by positional candidate cloning (1). Germline mutation of HRPT2 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome (HPT-JT), an autosomal dominant syndrome with high but incomplete penetrance (2). The major features are primary hyperparathyroidism (including 15% of all affected by HPT-JT with parathyroid cancer), jaw tumors, bilateral renal cysts, and, less commonly, solid renal tumors (2, 3). Germline inactivating HRPT2 mutation has also been reported in a minority of kindreds with familial isolated hyperparathyroidism (FIHP) (1, 4) and in up to 30% of patients with apparently sporadic parathyroid cancer (5, 6).HRPT2 encodes parafibromin, a 531 amino acid, putative tumor suppressor protein. Parafibromin demonstrates weak homology to Cdc73p, a budding yeast protein component of the RNA polymerase II-associated Paf1 complex. Recent evidence suggests that in humans, parafibromin interacts with RNA polymerase II via a human PAF1 complex whose other protein components include human Paf1, CTR9, Leo1 (7-9), and the WD40-repeat protein Ski8 (9). The molecular targets of parafibromin and the mechanism by which its inactivation can lead to neoplastic transformation are poorly understood. We show here that parafibromin, in the context of the PAF1 complex, mediates repression of the c-myc protooncogene through both transcriptional and posttranscriptional mechanisms. This finding provides a previously uncharacterized mechanism for the anti-proliferative action of parafibromin and a plausible mechanism by which its loss of function promotes neoplasia.

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Section: Resultssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 97%

The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

Zhang²,

Panicker³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…3c and ref. 32) exhibited a stronger interaction with mature p53 mRNA, confirming that the p53 mRNA-hCdc73 interaction occurred in the cytoplasm.…”

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confidence: 60%

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

Chung

Youn

et al. 2014

Nat Commun

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The parafibromin/hCdc73 is a component of the PAFc, which controls RNA polymerase II-mediated general transcription. In parathyroid carcinoma and familial autosomal dominant hyperparathyroidism-jaw tumour (HPT-JT), hCdc73 mutations are heavily implicated, yet the underlying mechanism of its carcinogenic action is poorly understood. Here we demonstrate that hCdc73 specifically controls messenger RNA stability of p53 and p53-mediated apoptosis. hCdc73 is associated with mature p53 mRNA in the cytoplasm and facilitates its degradation. Cytoplasmic hCdc73 physically interacts with eEF1Bg and hSki8, and this interaction is required to bind and destabilize p53 mRNA. Furthermore, enhanced association of p53 mRNA with a cancer-driven hCdc73(K34Q) mutant was also observed. As a result, reduced p53 expression as well as enhanced cell proliferation was acquired in the hCdc73 (K34Q)-overexpressed cells. Altogether, our findings indicate that hCdc73 directly targets p53 mRNA to repress p53 expression, and aberrant regulation of this interaction may lead to tumour progression.

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“…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].…”

Section: Functions Of Parafibromin the Protein Product Of Cdc73mentioning

confidence: 98%

“…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].…”

Section: Functions Of Parafibromin the Protein Product Of Cdc73mentioning

confidence: 99%

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

et al. 2010

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ABSTRACT:The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors in association with ossifying fibromas of the maxilla and/or mandible. The gene responsible for HPT-JT, known as CDC73, was identified in 2002 and encodes a 531 amino acid protein known as parafibromin. Parafibromin is predominantly a nuclear protein that interacts directly with b-catenin and also forms part of the RNA polymerase associated factor-1 complex (Paf1C) that regulates transcription. Heterozygous germline CDC73 mutations are detected in the majority of patients with HPT-JT, and the demonstration of loss of heterozygosity (LOH) at the CDC73 locus in tumors from affected individuals is consistent with a tumor suppressor role. Somatic CDC73 mutations are a frequent finding in nonfamilial (i.e., sporadic) parathyroid carcinomas and have also been reported in benign sporadic parathyroid tumors as well as sporadic renal and fibro-osseous jaw tumors. To date, 111 independent CDC73 mutations have been identified (68 germline; 38 somatic; 5 undefined), and these occur throughout the coding region and splice sites of the CDC73 gene, with the majority (480%) predicting premature truncation of the parafibromin protein. These CDC73 mutations, together with their clinical and biological relevance, are reviewed.

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Nuclear Localization of the Parafibromin Tumor Suppressor Protein Implicated in the Hyperparathyroidism-Jaw Tumor Syndrome Enhances Its Proapoptotic Function

Cited by 66 publications

References 27 publications

The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

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

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

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