Parafibromin inhibits cancer cell growth and causes G1 phase arrest

Zhang, Chun; Kong, Dong; Tan, Min‐Han; Pappas, Donald L.; Wang, Pengfei; Chen, Jindong; Farber, Leslie J.; Zhang, Nian; Koo, Han-Mo; Weinreich, Michael; Williams, Bart O.; Teh, Bin Tean

doi:10.1016/j.bbrc.2006.08.169

Cited by 79 publications

(62 citation statements)

References 19 publications

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“…were consistent with previous findings that transfection of wildtype, but not clinically significant patient-derived mutants of, parafibromin strongly inhibited cell growth in proliferation assays (11,12).…”

Section: Resultssupporting

confidence: 93%

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: 93%

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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“…This situation is not generally expected in the case of tumor suppressor gene inactivation, where loss of the normal function often is seen. However, a previous study has demonstrated in vitro expression of truncated parafibromin protein resulting from site-specific HRPT2 mutations introduced in a cell line, suggesting that HRPT2 mutated cells can still propel the production of parafibromin, albeit structurally defective (Zhang et al 2006). In our two cases with double mutations, this finding offers a possible explanation for the positive results obtained with the three most N-terminally located parafibromin antibodies.…”

Section: Discussionsupporting

confidence: 46%

“…In general, the complexity of parafibromin immunostaining might be aggravated by other factors. For example, increased proliferation can result from co-expression of mutant and wild-type parafibromin (Zhang et al 2006). Furthermore, parathyroid carcinomas reveal frequent gain of 1q, including the HRPT2 gene locus (Kytölä et al 2000), in contrast to the frequent observations of copy number losses at other tumor suppressor gene loci such as the MEN1 locus in parathyroid adenomas.…”

Section: Discussionmentioning

confidence: 99%

“…Its encoded protein parafibromin is a member of the polymerase-associated factor 1 (PAF1) complex associated with RNA polymerase II which regulates transcription elongation and histone modification (Carpten et al 2002, Rozenblatt-Rosen et al 2005, Yart et al 2005. In vitro studies have revealed dominant negative tumor suppressor properties (Zhang et al 2006), a functional nuclear localization signal (NLS; Hahn & Marsh 2005, Woodard et al 2005, Zhang et al 2006, Bradley et al 2007, and coupling to the wingless type (Wnt) signaling pathway (Mosimann et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification

Juhlin¹,

Villablanca²,

Sandelin³

et al. 2007

Endocr Relat Cancer

115

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Parafibromin is a protein product derived from the hyperparathyroidism 2(HRPT2) tumor suppressor gene and its inactivation has been coupled to familial and sporadic forms of parathyroid malignancy. In this study, we have conducted immunohistochemistry on 33 parathyroid carcinomas (22 unequivocal and 11 equivocal) using four parafibromin antibodies directed to different parts of the protein.Furthermore, for a fraction of cases, the immunohistochemical results were compared with known HRPT2 mutational status. Our findings show that 68% (15 out of 22) of the unequivocal carcinomas exhibited reduced expression of parafibromin while the 25 sporadic adenomas used as controls were entirely positive for parafibromin expression. Additionally, three out of the six carcinomas with known HRPT2 mutations showed reduced expression of parafibromin. Using all four antibodies, comparable results were obtained on the cellular level in individual tumors suggesting that there exists no epitope of choice in parafibromin immunohistochemistry. The results agree with the demonstration of a w60 kDa product preferentially in the nuclear fraction by western blot analysis. We conclude that parafibromin immunohistochemistry could be used as an additional marker for parathyroid tumor classification, where positive samples have low risk of malignancy, whereas samples with reduced expression could be either carcinomas or rare cases of adenomas likely carrying an HRPT2 mutation.

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“…Parafibromin overexpression was documented to induce cell cycle arrest in G1 phase by repressing cyclin D1 via histone H3K9 methylation, indicating that parafibromin has a critical role in cell cycle (Zhang et al, 2006;Yang et al, 2010). Parafibromin or Paf1 knockdown was proved to stimulate cell proliferation and increase the c-myc level by stabilizing c-myc protein and activating the c-myc promoter (Lin et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Effects of Parafibromin Expression on the Phenotypes and Relevant Mechanisms in the DLD-1 Colon Carcinoma Cell Line

Zhao¹,

Sun²,

Zhu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Parafibromin is a protein encoded by the HRPT2 (hyperparathyroidism 2) oncosuppressor gene and its down-regulated expression is involved in pathogenesis of parathyroid, breast, gastric and colorectal carcinomas. This study aimed to clarify the effects of parafibromin expression on the phenotypes and relevant mechanisms of DLD-1 colon carcinoma cells. Methods: DLD-1 cells transfected with a parafibromin-expressing plasmid were subjected to examination of phenotype, including proliferation, differentiation, apoptosis, migration and invasion. Phenotype-related proteins were measured by Western blot. Parafibromin and ki-67 expression was detected by immunohistochemistry on tissue microarrays. Results: The transfectants showed higher proliferation by CCK-8, better differentiation by electron microscopy and ALP activity and more apoptotic resistance to cisplatin by DNA fragmentation than controls. There was no difference in early apoptosis by annexin V, capase-3 activity, migration and invasion between DLD-1 cells and their transfectants. Ectopic parafibromin expression resulted in down-regulated expression of smad4, MEKK, GRP94, GRP78, GSK3β-ser9, and Caspase-9. However, no difference was detectable in caspase-12 and -8 expression. A positive relationship was noted between parafibromin and ki-67 expression in colorectal carcinoma. Conclusions: Parafibromin overexpression could promote cell proliferation, apoptotic resistance, and differentiation of DLD-1 cells.

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Parafibromin inhibits cancer cell growth and causes G1 phase arrest

Cited by 79 publications

References 19 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

Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification

Effects of Parafibromin Expression on the Phenotypes and Relevant Mechanisms in the DLD-1 Colon Carcinoma Cell Line

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