Influence of Calcium and 1,25-Dihydroxycholecalciferol on Proliferation and Proto-Oncogene Expression in Primary Cultures of Bovine Parathyroid Cells*

Kremer, Richard; Bolivar, Isabel; Goltzman, David; Hendy, Geoffrey N.

doi:10.1210/endo-125-2-935

Cited by 211 publications

(98 citation statements)

References 31 publications

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“…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). Given the inhibition of c-myc expression by endogenous parafibromin and Paf1 demonstrated here, the inactivation of parafibromin in human parathyroid and other tumors is likely to promote neoplasia at least in part because of such loss-of-function.…”

Section: Discussionmentioning

confidence: 66%

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: Discussionmentioning

confidence: 66%

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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“…Sufficient 1,25(OH) 2 D 3 suppresses not only PTH synthesis at the mRNA level but also PT cell proliferation through the VDR (13,14). Previous work also indicates the involvement of VDR down-regulation in the high proliferative activity of PTGs in 28HPT (16).…”

Section: Discussionmentioning

confidence: 93%

“…VDR gene knockout mice have a similar phenotype (12). Vitamin D suppresses not only PTH synthesis at the mRNA level but also PT cell proliferation (13,14). In addition, VDR expression has been shown to be correlated negatively with PT growth potential in hemodialysis patients with 28HPT (7,15,16).…”

Section: Introductionmentioning

confidence: 99%

Decrease in vitamin D receptor and calcium-sensing receptor in highly proliferative parathyroid adenomas

Yano

Sugimoto

Tsukamoto

et al. 2003

European Journal of Endocrinology

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Objective: A significant decrease in vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) protein expression has been demonstrated recently in parathyroid (PT) adenomas. In this study, we investigated the relationships between the proliferative activity of parathyroid glands (PTGs) and the expression of VDR as well as CaSR, and compared it with the clinical severity in patients with primary hyperparathyroidism (18HPT). Design: Seven patients with 18HPT were included in this study. Four patients with thyroid carcinoma served as controls. Methods: Immunohistochemical staining was performed on serial sections of PTGs with specific antibodies against CaSR, VDR, and Ki67. Areas examined in each section were selected at random in relation to the gland size. The number of Ki67-positive cells was expressed as a labeling index (LI; positive cells per 1000 PT cells). The expression of CaSR and VDR was semi-quantitatively analyzed based on the intensity of staining. After averages of the scores from all areas were calculated, CaSR and VDR scores, and Ki67 LI were assigned to each gland for use in statistical analyses. Results: In PT adenomas, scores of VDR and CaSR were markedly lower than in normal PTGs ðP , 0:01Þ; while the proportion of Ki67-positive cells in PT adenomas was significantly higher than in normal PTGs ðP , 0:01Þ: Single regression analyses revealed that Ki67 LI was positively correlated with serum levels of intact parathyroid hormone and Ca, and PTG weight (R ¼ 0:70; P , 0:05; R ¼ 0:78; P , 0:01 and R ¼ 0:84; P , 0:05 respectively). Ki67 LI was negatively correlated with CaSR and VDR scores (R ¼ 20:78; P , 0:01 and R ¼ 20:72; P , 0:05 respectively). Moreover, there was a strong positive relationship between CaSR and VDR expression ðR ¼ 0:95; P , 0:001Þ: Conclusions: Marked decreases in VDR and CaSR expression could, at least in part, be responsible for the high proliferation of PT cells and the pathological progression of 18HPT.

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“…As demonstrated in the present study, the effects of vitamin D 3 and retinoids seem to include inhibition of parathyroid chief cell proliferation. Molecular mechanisms for the effect of vitamin D 3 on parathyroid cell proliferation may include the c-myc gene (Kremer et al 1989). Retinoic acids have previously been shown to affect proliferation of many tumor cell lines, and the mechanisms for such effects may be several (Nagy et al 1998, Singh & Lippman 1998).…”

Section: +mentioning

confidence: 99%

Differentiation of human parathyroid cells in culture

Liu¹,

Ridefelt²,

Åkerström³

et al. 2001

Journal of Endocrinology

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Continuous culture of parathyroid cells has proven difficult, regardless from which species the cells are derived. In the present study, we have used a defined serum-free low calcium containing medium to culture human parathyroid cells obtained from patients with parathyroid adenomas due to primary hyperparathyroidism. No fibroblast overgrowth occurred, and the human parathyroid chief cells proliferated until confluent. After the first passage the cells ceased to proliferate, but still retained their functional capacity up to 60 days, demonstrated by Ca 2+ -sensitive changes in the release of parathyroid hormone (PTH) and as adequate cytoplasmic calcium ([Ca 2+ ] i ) responses to changes in ambient calcium as measured by microfluorimetry. Low calcium concentrations enhanced, and vitamin D 3 and retinoic acids (RA) dose-dependently inhibited cell proliferation during the first passage, as determined by [ 3 H]thymidine incorporation, immunohistochemistry for proliferating cell nuclear antigen and cell counting. Signs of differentiation were present as the set-points, defined as the external calcium concentration at which half-maximal stimulation of [Ca 2+ ] i (set-point c ), or half-maximal inhibition of PTH release (set-point p ) occur, were higher in not proliferating compared with proliferating cells in P0. Inhibition of cell proliferation was accompanied by signs of left-shifted set-points, indicating a link between proliferation and differentiation.The results demonstrate that human parathyroid chief cells cultured in a defined serum-free medium can be kept viable for a considerable time, and that signs of differentiation occur after proliferation has ceased. The low calcium stimulated cell proliferation may also be inhibited by vitamin D and RA.

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Influence of Calcium and 1,25-Dihydroxycholecalciferol on Proliferation and Proto-Oncogene Expression in Primary Cultures of Bovine Parathyroid Cells*

Cited by 211 publications

References 31 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

Decrease in vitamin D receptor and calcium-sensing receptor in highly proliferative parathyroid adenomas

Differentiation of human parathyroid cells in culture

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