Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The properties of neoplastic proliferation and hormonal dysregulation are tightly linked in primary hyperparathyroidism (HPT). However, whether abnormal parathyroid proliferation is the cause or result of a shift in calcium-sensitive parathyroid hormonal regulation has been controversial. We addressed this issue by analyzing the temporal sequence of these fundamental abnormalities in a mouse model of primary HPT. These transgenic mice (PTH-D1) harbor a transgene that targets overexpression of the cyclin D1 oncogene to parathyroid cells, resulting in parathyroid hypercellularity with a phenotype of chronic biochemical HPT and, notably, an abnormal in vivo PTH-calcium set point. We examined parathyroid cell proliferation and biochemical alterations in PTH-D1 and control wild-type mice from ages 1-14 months. Strikingly, abnormal parathyroid proliferation regularly preceded dysregulation of the calcium-PTH axis, supporting the concept that disturbed parathyroid proliferation is the crucial primary initiator leading to the development of the biochemical phenotype of HPT. Furthermore, we observed that decreased expression of the calcium-sensing receptor in the parathyroid glands occurs several months before development of biochemical HPT, suggesting that decreased calcium-sensing receptor may not be sufficient to cause PTH dysregulation in this animal model of primary HPT.
Mol Endocrinol 2005 Oct
PMID:Abnormal parathyroid cell proliferation precedes biochemical abnormalities in a mouse model of primary hyperparathyroidism. 1592 11

Single photon emission tomography (SPET) represents an indispensable diagnostic tool in nuclear medicine. Due to better contrast resolution, cross sectional and 3D images, SPET plays a useful complementary tool to bidimensional planar scintigraphy in certain clinical conditions, while representing the procedure of choice in others. However, high resolution SPET with pinhole collimator (P-SPET) can improve conventional SPET sensitivity with parallel hole collimators. This review summarizes data on the employment of conventional SPET and P-SPET in breast cancer, differentiated thyroid cancer (DTC) and hyperparathyroidism patients, using the cationic lipophilic complexes [(99m)Tc]metoxy isobutyl isonitrile (sestaMIBI) and [(99m)Tc]tetrofosmin as oncotropic radiotracers. In breast cancer patients, SPET with these radiotracers can play an important complementary role to planar scintimammography in detecting primary tumors, especially when non palpable and small in size, whereas SPET and particularly P-SPET represents the procedure of choice in preoperative axillary lymph node status evaluation in which planar is almost always irrelevant. In DTC follow-up patients, SPET and P-SPET with cationic lipophilic radiotracers are indicated in both locoregional and distant metastasis detection, especially in patients with high Tg serum levels and negative radioiodine scanning in whom these procedures represent a reliable alternative to diagnostic (131)I scanning. Moreover, the combined use of [(99m)Tc]tetrofosmin P-SPET and US can identify recurrences and lymph node metastases in the neck, both fixing and non fixing iodine, downstaged or negative at (131)I scanning. SPET can also be a useful complementary tool to planar parathyroid scintigraphy in the detection and localization of small and ectopic parathyroid adenomas in the neck or mediastinum, while neck P-SPET seems to also significantly increase planar sensitivity in hyperplastic glands. SPET and P-SPET are indicated in persistent and recurrent hyperparathyroidism including from carcinoma.
Q J Nucl Med Mol Imaging 2005 Jun
PMID:99mTc labelled cationic lipophilic complexes in malignant and benign tumors: the role of SPET and pinhole-SPET in breast cancer, differentiated thyroid carcinoma and hyperparathyroidism. 1601 Feb 52

Precise localization of parathyroid glands using 99mTc-labeled hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy could be affected by various biological factors. There is increasing evidence that radiotracer retention could be controlled by members of multidrug resistance (MDR) system, especially P-glycoprotein (P-gp). Since the role of P-gp in tertiary hyperparathyroidism (T-HPTH) scintigraphic studies is poorly recognized, the aim of the study was to compare the correlation between parathyroid P-gp expression and results of their scintigraphy in T-HPTH versus primary hyperparathyroidism (P-HPTH). P-HPTH (n = 19) and T-HPTH (n = 18) patients were subjected to 99mTc-MIBI scintigraphy followed by surgical treatment. The parathyroid glands were assessed in routine hematoxylin-eosin staining and P-gp expression was analyzed using immunohistochemistry. Parathyroids collected during cadaver donor multi-organ harvesting were used as a control. It has been found that P-HPTH-derived parathyroid glands with predominating adenoma morphology expressed less P-gp, as compared to P-gp-rich T-HPTH glands, mainly displaying nodular or diffused hyperplasia phenotype. This finding reversely correlated with results of 99mTc-MIBI scintigraphy. However, we did not observe any difference in P-gp expression nor scintigraphy result between nodular or diffused hyperplasia. Altogether, these data suggest that P-gp overexpression in T-HPTH could be responsible for decreased sensitivity of 99mTc-MIBI scintigraphy in those patients. Therefore, the recently proposed reduced neck exploration or limited parathyroid resection on the basis of scintigraphy could create the risk of persisted/recurrent hyperparathyroidism. However, this problem requires further study.
Int J Mol Med 2005 Aug
PMID:P-glycoprotein expression influences the result of 99mTc-MIBI scintigraphy in tertiary hyperparathyroidism. 1601 52

Therapeutic trials of 1alpha,25(OH)(2)D(3) and related synthetic analogs are merited in diverse clinical fields, including treatment or prevention of bone disease, cancer, immune-mediated diseases, cardiovascular diseases, and prostatic hypertrophy. Potential difficulties of carrying out such trials successfully, include experimental data suggesting relatively modest therapeutic effects of 1alpha,25(OH)(2)D(3) analogs as stand-alone intervention and the likely requirement for large study group size and lengthy follow-up periods, if individual prophylactic effects are to be proven. Thus, it may be wise to identify patient groups with multiple potential benefits, accelerated disease risks, and the possibility for exploring synergistic pharmacological effects, in whom to carry out clinical trials of 1alpha,25(OH)(2)D(3) analogs. With this consideration in mind, the suitability of kidney transplant recipients for such studies is discussed. Although, highly effective in reversing end-stage renal disease, kidney transplantation continues to be limited by heightened risk of osteoporosis, persistent hyperparathyroidism, acute and chronic immunological injury, new cancer diagnosis, and cardiovascular events. In addition, kidney transplant recipients generally receive multiple immunosuppressants with a high prevalence of medication-related toxicities. Finally, it is pointed out that clinical trials carried out in organ transplant recipients provide a unique opportunity for longitudinal comparison of target tissue structural and gene expression profiles among treated and control patient groups. It is proposed that addition of a 1alpha,25(OH)(2)D(3) analog to conventional post-kidney transplant medication regimens is likely to be associated with measurable effects to prevent or retard multiple important complications and that this patient group is especially suitable for carrying out clinical trials of these compounds.
J Steroid Biochem Mol Biol 2005 Oct
PMID:Multiple potential clinical benefits for 1alpha,25-dihydroxyvitamin D3 analogs in kidney transplant recipients. 1602 80

The parathormone (PTH) production is controlled by calcium and vitamin D, which interact with the calcium-sensing receptor (CaSR) and vitamin D receptor (VDR), respectively. All of these elements control calcium homeostasis, which is crucial for many physiological processes. Thus, impairment of the upstream component of this system, e.g. a decrease of CaSR and/or VDR, could result in hyperparathyroidism (HPTH). Therefore, the aim of this study was to assess the expression of CaSR and VDR in a tertiary form of HPTH (T-HPTH). The study involved 19 T-HPTH patients qualified for parathyroidectomy and 21 control parathyroids harvested from multi-organ cadaver donors. The small fragments of harvested glands were homogenized and used for Western blot analysis, whereas the remaining tissues underwent routine hematoxylin-eosin staining or immunostaining for CaSR and VDR. Among 64 T-HPTH parathyroids, 58 revealed the morphology of benign hyperplasia, 2 were identified as adenoma and 4 were classified as normal; some glands displayed a mixed histological phenotype. Western blot analysis revealed a decrease of CaSR and VDR in hyperplasia and adenoma-derived samples. However, no correlation between the types of hyperplasia and receptor expression was observed. On the other hand, microscopic analysis of CaSR- and VDR-immunostained sections revealed a highly differentiated and significantly decreased mean expression of both receptors, which correlated with parathyroid histology. The reason behind the impaired expression of CaSR and VDR in T-HPTH is unclear. It presumably results from constant parathyroid stimulation at the stage of S-HPTH, followed by further development of polyclonal autonomy. However, the verification of this thesis requires further study.
Int J Mol Med 2006 May
PMID:The calcium-sensing receptor and vitamin D receptor expression in tertiary hyperparathyroidism. 1659 60

1Alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3; calcitriol] is best known as a hormone involved in calcium homeostasis but is also a potent antiproliferative agent in many cell types, particularly epithelial cells. 1Alpha,25(OH)2D3 mediates its actions through a classic steroid hormone-like transcriptional mechanism by influencing the expression of hundreds of genes. Effects of 1alpha,25(OH)2D3 have been observed on expression of cell cycle regulators, growth factors and their receptors, apoptotic machinery, metastatic potential, and angiogenesis; all of which have some effect on hyperproliferative conditions. This minireview focuses on the anticancer potential of 1alpha,25(OH)2D3 and its analogues by summarizing the promising data from animal and human trials of 1alpha,25(OH)2D3 and some of the more interesting synthetic vitamin D analogues in the treatment of a variety of different animal cancer models and in human patients with advanced cancer. Optimal administration of vitamin D analogues is only just being achieved with high-dose intermittent administration overcoming bioavailability and hypercalcemia problems and combination therapy with cytotoxic agents (taxols and cisplatins), antiresorptive agents (bisphosphonates), or cytochrome P450 inhibitors being attempted. Although the potential of vitamin D as an antiproliferative drug has been realized in the treatment of psoriasis and in parathyroid cell hyperplasia associated with secondary hyperparathyroidism, the search for an anticancer treatment incorporating a vitamin D analogue remains elusive.
Mol Cancer Ther 2006 Apr
PMID:Promise of vitamin D analogues in the treatment of hyperproliferative conditions. 1664 49

Hyperparathyroidism (HPT) can be associated with muscle atrophy and weakness. Muscle atrophy is typically caused by increased muscle protein breakdown. The influence of HPT on calpains and the ubiquitin-proteasome pathway, which are important regulators of muscle proteolysis, is not yet known. We examined the expression in skeletal muscle of mu- and m-calpain and the ubiquitin ligases, atrogin-1 and MuRF1, in patients with primary HPT. A biopsy was obtained from the sternohyoid muscle in patients undergoing surgery for primary HPT (n=8) and in normocalcemic control patients undergoing thyroid surgery (n=11). mRNA levels for atrogin-1, MuRF1 and the calcium-regulated proteases, mu- and m-calpain, were determined by real-time PCR. Calpain activity was measured using the calpain-specific substrate, BODIPY-FL-casein, and by zymography. Serum calcium was 11.4+/-0.46 and 9.5+/-0.10 mg/dl in HPT and control patients, respectively (p<0.01). The corresponding phosphate levels were 2.7+/-0.2 and 3.6+/-0.1 mg/dl (p<0.05). Parathyroid hormone serum concentration was 286+/-103 pg/ml (range, 77-946 pg/ml) in patients with HPT and was not measured in control patients. There were no significant differences in mRNA levels for atrogin-1, MuRF1, mu- or m-calpain and in calpain activity between HPT and control patients. The results suggest that the ubiquitin-proteasome and calpain systems are not activated in skeletal muscle in patients with primary HPT, at least not in patients with moderate hypercalcemia.
Int J Mol Med 2006 Sep
PMID:The gene expression and activity of calpains and the muscle wasting-associated ubiquitin ligases, atrogin-1 and MuRF1, are not altered in patients with primary hyperparathyroidism. 1686 32

The extracellular calcium-sensing receptor (CaR), a G protein-coupled receptor that resides on the parathyroid cell surface negatively regulates secretion of parathyroid hormone (PTH). The CaR is functionally expressed in bone, kidney, and gut--the three major calcium-translocating organs involved in calcium homeostasis. Further studies are needed to define fully the homeostatic roles of the CaR in tissues that are involved in systemic extracellular calcium [Ca(2+)](o) homeostasis. The role of the CaR in regulating calcium metabolism has been greatly clarified by the identification and studies of genetically determined disorders that either activate or inactivate the receptor. Antibodies to the CaR that either activate or inactivate it produce syndromes resembling the corresponding genetic diseases. Expression of the CaR is significantly reduced in primary and secondary hyperparathyroidism, which could contribute to the defective [Ca(2+)](o)-sensing in these conditions. Calcimimetics act as CaR agonists or allosteric activators and thereby potentiate the effects of [Ca(2+)](o) on parathyroid cell function. This kind of pharmacological manipulation of the CaR is now used for the treatment of hyperparathyroid states, whereby the calcimimetics increase the activation of the CaR at any given level of extracellular calcium. Calcimimetics are also an effective element in the treatment of secondary hyperparathyroidism, particularly in dialysis patients, by virtue of reducing plasma levels of PTH, calcium and phosphate.
Mol Genet Metab 2006 Nov
PMID:Role of calcium-sensing receptor in mineral ion metabolism and inherited disorders of calcium-sensing. 1691 92

Germline knockout of the extracellular Ca2+ -sensing receptor (CaR) leads to a phenotype that includes severe hypercalcemia, hyperparathyroidism, relative hypocalciuria, skeletal abnormalities, retarded growth, and early postnatal death. To investigate the role of heterotrimeric G proteins in CaR signaling, we used cre/lox technology to delete the respective alpha-subunits of Gq and G11 selectively in parathyroid cells. Mice that were PTH-Cre(+/-); Gnaq(flox/flox); Gna11(-/-) (PTH-Galphaq/Galpha11 -double knockouts) were viable, but showed all the features of germline knockout of the CaR except hypocalcuria. Our results demonstrate the critical role of both Gq and G11 in mediating inhibition of PTH secretion by extracellular Ca2+.
Mol Endocrinol 2007 Jan
PMID:Parathyroid-specific double knockout of Gq and G11 alpha-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2+ -sensing receptor. 1698

Familial hyperparathyroidism, a disease of the parathyroid glands, may occur in conjunction with pituitary and pancreatic tumors (multiple endocrine neoplasia type I), kidney and bone tumors (hyperparathyroidism jaw tumor syndrome), or alone (familial isolated hyperparathyroidism). This study describes the development and validation of rapid scanning for mutations in two tumor suppressor genes linked to familial hyperparathyroidism-MEN1 and HRPT2. Denaturing high-performance liquid chromatography mutation scanning for MEN1 was performed using a set of 10 amplicons covering the nine coding exons and flanking intronic regions and for HRPT2 using a set of three amplicons for exons 1, 2, and 7 and flanking intronic regions, in which 80% of the mutations identified to date are located. All 52 MEN1 mutations or polymorphisms, 46 known and six unknown, were successfully detected. Mutation detection in exon 9 was not confounded by the presence of the common polymorphism D418D. In addition, all 10 HRPT2 mutations were successfully detected, and a two-step approach was able to distinguish IVS2 common polymorphisms from exon 2 mutations. The development of rapid denaturing high performance liquid chromatography mutation scanning of MEN1 and HRPT2 facilitates a molecular diagnosis of the associated familial syndromes for both clinically affected and at-risk family members.
J Mol Diagn 2006 Nov
PMID:Rapid mutation screening for HRPT2 and MEN1 mutations associated with familial and sporadic primary hyperparathyroidism. 1706 24


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