Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTH-like peptide (PLP) is produced by a number of tumors commonly associated with the development of hypercalcemia. Analysis of the expression of the PLP gene has demonstrated that a variety of non-neoplastic endocrine and nonendocrine tissues contain PLP mRNA transcripts. Using a combination of Northern blot analysis, immunohistochemistry, and RIAs, we have demonstrated that the PLP gene is expressed in normal human and rat fetal and adult islets of Langerhans. PLP gene expression was not confined to cells containing a single pancreatic islet hormone, but was found in cells of all four major endocrine subtypes. PLP mRNA transcripts were also detected in RNA prepared from isolated rat islets, and small amounts of PLP immunoreactivity were secreted by cultured rat islets. Fifteen human pancreatic endocrine tumors not associated with hypercalcemia were analyzed and PLP-immunopositive tumor cells were found in 13. These observations demonstrate that the PLP gene is expressed in the normal and neoplastic islets of Langerhans, and suggests a possible role for this peptide in the growth or function of the endocrine pancreas.
Mol Endocrinol 1989 Oct
PMID:The parathyroid hormone-like peptide gene is expressed in the normal and neoplastic human endocrine pancreas. 269 79

A rat Leydig cell tumor cDNA library was screened with a 32P-labeled genomic restriction fragment encoding human PTH-like peptide (hPLP), and three cDNA clones were isolated. The largest cDNA insert contained 1146 nucleotides. The cloned cDNA encodes a 177-amino acid protein consisting of a predicted 36-amino acid leader sequence and a 141-amino acid mature peptide in which 9 of 13 amino-terminal residues are identical to rat PTH (rPTH). Comparison of rPLP with hPLP reveals marked conservation of both the nucleotide and amino acid sequences through the prepro, amino-terminal, and midregion portions of the molecules. There is also striking conservation of the 3' noncoding regions of rPLP and hPLP mRNAs, both of which contain AU-rich repeated sequences that may affect mRNA stability. A single species of mRNA of approximately 1.4-kilobases was identified in the rat Leydig cell tumor and in normal rat stomach. Southern blot analysis is consistent with the presence of a single copy of the rPLP gene per haploid genome, and there is no major rearrangement or amplification of the rPLP gene in DNA isolated from the tumor per se. The results demonstrate the presence of a single gene transcript in a rat model of malignancy associated with hypercalcemia which encodes a peptide homologous to hPLP, document the marked interspecies sequence conservation that exists in major functional domains of the mRNAs and peptides, and show the expression of mRNA encoding rPLP in normal stomach as well as in neoplastic rat tissue.
Mol Endocrinol 1989 Mar
PMID:Rat parathyroid hormone-like peptide: comparison with the human homologue and expression in malignant and normal tissue. 274 58

In order to suppress the parathyroid glands by inducing hypercalcemia, young rats were fed a diet containing a low (0.02%) phosphate content. After 28 days blood samples were taken for estimation of serum calcium, phosphate and immunoreactive parathyroid hormone levels. Both parathyroids from each animal were subjected to serial sectioning so that the total glandular volume could be calculated by light microscopy. Volume and surface densities of cells and organelles were measured according to conventional stereological principles, so that the total volumes and surface areas could be estimated. Phosphate depletion caused marked growth retardation. The animals also developed hypophosphatemia, but in spite of pronounced hypercalcemia the levels of circulating immunoreactive parathyroid hormone remained unchanged. The volume of the parathyroids was reduced, but only to an extent commensurate with the reduced body mass. In the experimental group the volume density of cells was unchanged, but that of nuclei was increased; the volume density of Golgi complexes was reduced. The densities of the other cell components measured, namely the volume density of mitochondria and the surface densities of secretory cells, nuclear membranes and rough endoplasmic reticulum were unchanged. When the volumes and surfaces were expressed in absolute terms and related to total body mass, no differences between the groups were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)
Virchows Arch B Cell Pathol Incl Mol Pathol 1988
PMID:Stereological studies of the parathyroids in the young rat with hypercalcemia induced by severe phosphate depletion. 290 Nov 63

We undertook this study to determine the effects of a transplantable Leydig cell tumor on the major digestive glands of the host rats. It has been known that after bearing this tumor for only two weeks, the rats become anorexic and cathectic, develop hypercalcemia and osteolysis, and their peripheral bone marrow becomes hyperplastic. We now demonstrate that the parotid glands undergo marked degeneration including depletion of secretory product, apparent loss of acinar organization and the appearance of conjoined nuclei. The submandibular and sublingual glands and the pancreas are virtually unaffected. The liver undergoes fatty degeneration, the Kupffer cells become more prominent and more numerous, and the sinusoids sometimes contain small islets of hemopoietic tissue.
Virchows Arch B Cell Pathol Incl Mol Pathol 1982
PMID:Degenerative changes in the digestive glands of rats bearing Leydig cell tumors. 612 39

Parathyroid hormone-related peptide (PTHrP) is a mediator of cellular growth and differentiation as well as a cause of malignancy-induced hypercalcemia. Most of the actions of PTHrP have been attributed to its interaction with a specific cell surface receptor that binds the N-terminal domain of the protein. Here we present evidence that PTHrP promotes some of its cellular effects by translocating to the nucleolus. Localization of transiently expressed PTHrP to the nucleolus was dependent on the presence of a highly basic region at the carboxyl terminus of the molecule that bears homology to nucleolar targeting sequences identified within human retroviral (human immunodeficiency virus type 1 and human T-cell leukemia virus type 1) regulatory proteins. Endogenous PTHrP also localized to the nucleolus in osseous cells in vitro and in vivo. Moreover, expression of PTHrP in chondrocytic cells (CFK2) delayed apoptosis induced by serum deprivation, and this effect depended on the presence of an intact nucleolar targeting signal. The present findings demonstrate a unique intracellular mode of PTHrP action and a novel mechanism by which this peptide growth factor may modulate programmed cell death.
Mol Cell Biol 1995 Aug
PMID:Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. 762 2

Parathyroid hormone-related protein (PTHrP) was discovered as a hypercalcemia-inducing product of malignant cells and has since been demonstrated to be a product of many tissues. Although it is robustly expressed in fetal lung, PTHrP expression has not been assigned to alveolar epithelial cells in adult lung. We have shown that PTHrP is expressed in the adult rat lung and by cultured rat alveolar type II epithelial cells with sensitive and specific immunoassays and immunohistochemical techniques. Immunoassay of cell extracts demonstrated that freshly isolated type II cells contained PTHrP (136 pg/10(7) cells), whereas freshly isolated alveolar macrophages and cultured macrophages did not express PTHrP. Cultured type II cells secreted PTHrP into medium, 202 +/- 11 fg PTHrP/micrograms cell protein in 24 h. Basal secretion remained stable up to 7 days in culture. Treatment with phorbol myristate acetate or 1-oleoyl-2-acetyl-sn-glycerol produced a dose-related, 2- to 4-fold increase in PTHrP secretion. However, forskolin, ionomycin, ATP, phenylephrine, capsaicin, and bradykinin had no effect. Thus, PTHrP secretion appeared to be regulated by a protein kinase C-dependent pathway. PTHrP could also be demonstrated in pulmonary lavage fluid. Although the function of PTHrP in the adult lung is unknown, it could involve control of cell growth and differentiation or control of surfactant lipid secretion. Further studies are necessary to elucidate the function of PTHrP in the lung.
Am J Respir Cell Mol Biol 1994 Dec
PMID:Alveolar epithelial cells express and secrete parathyroid hormone-related protein. 794 99

The cholecalciferol analogues 1(S),3(R)-dihydroxy-20(R)-[3'(S)-cyclopropyl-3'-hydroxyprop-1'(E)- enyl]-9,10-secopregna-5(Z),7(E),10(19)-triene (calcipotriol, MC 903), 1(S),3(R)-dihydroxy-20(R)-[3'-ethyl-3'-hydroxy- pentoxy]-9,10-secopregna-5(Z),7(E),10(19)-triene (KH 1060) and 1(S),3(R)-dihydroxy-20(R)-[5'-ethyl-5'-hydroxy-hepta- 1',3'(E)-diene-1'-yl]-9,10-secopregna-5(Z),7(E),10(19)-triene (EB 1089) have been modified in the side chain to increase their effects on cell differentiation and proliferation and to reduce the risk of inducing hypercalcemia. The effects of these analogues were tested on FRTL-5 cells, a strain of continuously growing and well-differentiated rat thyroid cells. FRTL-5 cells express a normal vitamin D receptor (VDR), and 1,25-(OH)2D3 potently attenuates the thyrotropin (TSH) stimulated production of the intracellular signalling molecule 3',5'-cyclic adenosine monophosphate (cAMP), iodide uptake and cell growth of these cells. These effects were also induced by the cholecalciferol analogues after 4 days of incubation. KH 1060 was the biologically most potent of the analogues and, compared to KH 1060, the IC50 values were 1.2-, 2.7- and 14-fold higher when 1,25-(OH)2D3, EB 1089 and MC 903, respectively, were used for the displacement of receptor bound [3H]1,25-(OH)2D3. As indicated by their VDR binding, 1,25-(OH)2D3 and EB 1089 were equipotent inhibitors of the TSH stimulated adenylyl cyclase activity, iodide uptake and FRTL-5 cell growth. The analogue MC 903 was the second most potent inhibitor of cell growth in spite of expressing the lowest affinity for the VDR and the weakest inhibition of TSH-stimulated adenylyl cyclase activity and iodide uptake. In conclusion, the biological effects of these cholecalciferol analogues in rat thyroid FRTL-5 cells seem to be mainly determined by their binding affinity for the VDR, although non-genomic effects can not be excluded.
J Steroid Biochem Mol Biol 1994 Aug
PMID:Vitamin D receptor binding and biological effects of cholecalciferol analogues in rat thyroid cells. 804 43

Parathyroid hormone-related peptide (PTHrP) is thought to be responsible for hypercalcemia in some patients with malignant tumors. The PTHrP gene has seven exons, giving rise to three types of PTHrP isoform through alternative splicing. We studied the expression of mRNAs in 14 human cell lines using the reverse transcription-PCR method, to examine tissue-specific expression. All the cell lines expressed at least two types of PTHrP transcript. Most cell lines expressed all four types of PTHrP mRNA isoform. However, a rhabdomyosarcoma cell line, RD, and a bladder carcinoma cell line, T24, expressed only two types. These results may suggest that PTHrP mRNA is expressed in the majority of tumor and normal tissues and that it shows less tissue- or tumor-specificity.
J Mol Endocrinol 1995 Dec
PMID:Multiple alternative splice isoforms of parathyroid hormone-related peptide mRNA in human cell lines. 874 30

1alpha,25(OH)2-16-ene-D3, a synthetic analog of the steroid hormone, 1alpha,25(OH)2D3, has great potential to become a drug in the treatment of leukemia and other proliferative disorders, because of its minimal in vivo calcemic activity associated with a potent inhibitory effect on cell growth. However, at present, the mechanisms through which 1alpha,25(OH)2-16-ene-D3 expresses its biological activities are still not completely understood. Our previous in vitro study in a perfused rat kidney indicated for the first time that 1alpha,25(OH)2-16-ene-D3 and 1alpha,25(OH)2D3 are metabolized differently. 1alpha,25(OH)2-24-oxo-16-ene-D3, an intermediary metabolite of 1alpha,25(OH)2-16-ene-D3 formed through the C-24 oxidation pathway, accumulated significantly in the perfusate when compared to 1alpha,25(OH)2-24-oxo-D3, the corresponding intermediary metabolite of 1alpha,25(OH)2D3. In a subsequent in vivo study, we also reported that 1alpha,25(OH)2-24-oxo-16-ene-D3 exerted immunosuppressive activity equal to its parent, without causing significant hypercalcemia. In order to establish further the critical role of 1alpha,25(OH)2-24-oxo-16-ene-D3, in generating some of the key biological activities ascribed to its parent, we performed the present in vitro study using a human myeloid leukemic cell line (RWLeu-4) as a model. Comparative target tissue metabolism studies indicated that 1alpha,25(OH)2-16-ene-D3 and 1alpha,25(OH)2D3 are metabolized differently in RWLeu-4 cells, and the differences were similar to the ones we previously observed in the rat kidney. The significant finding was the accumulation of 1alpha,25(OH)2-24-oxo-16-ene-D3 in RWLeu-4 cells because of its resistance to further metabolism. Biological activity studies indicated that both 1alpha,25(OH)2-16-ene-D3 and its 24-oxo metabolite produced growth inhibition and promoted differentiation of RWLeu-4 cells to the same extent, and these activities were several fold higher than those exerted by 1alpha,25(OH)2D3. In addition, the genomic action of each vitamin D compound was assessed in a rat osteosarcoma cell line (ROS 17/2.8) by measuring its ability to transactivate a gene construct containing the vitamin D response element of the osteocalcin gene linked to the growth hormone reporter gene. In these studies, both 1alpha,25(OH)2-16-ene-D3 and its 24-oxo metabolite exerted similar but potent transactivation activity which was several fold greater than that exerted by 1alpha,25(OH)2D3 itself. In summary, our results indicate that the production and slow clearance of the bioactive intermediary metabolite, 1alpha,25(OH)2-24-oxo-16-ene-D3, in RWLeu-4 cells contributes significantly to the final expression of the enhanced biological activities ascribed to its parent analog, 1alpha,25(OH)2-16-ene-D3.
J Steroid Biochem Mol Biol 1996 Dec
PMID:1alpha,25-dihydroxy-24-oxo-16-ene vitamin D3, a metabolite of a synthetic vitamin D3 analog, 1alpha,25-dihydroxy-16-ene vitamin D3, is equipotent to its parent in modulating growth and differentiation of human leukemic cells. 901 Mar 46

Activating germline mutations in the cysteine-rich domain of the RET proto-oncogene are found in >92% of the cases of multiple endocrine neoplasia type 2A (MEN2A) and 85% of familial medullary thyroid carcinoma (FMTC). In virtually 100% of patients with identified mutations one of five cysteines is altered by a missense mutation. In a MEN2A family with 14 affected and 11 unaffected living members, hypercalcemia was diagnosed in eight patients and histological evaluation revealed parathyroid hyperplasia in all cases examined (10/10). No member of this family showed any evidence for the existence of pheochromocytoma. This is the first documentation of a family without pheochromocytoma but with a high incidence of parathyroid disease. Genetic analysis revealed the presence of an unusual heterozygous mutation in exon 11 of the RET proto-oncogene representing a duplication of 12 bp resulting in the insertion of four amino acids between codon 634 (Cys) and 635 (Arg), thus creating an additional cysteine residue.
Hum Mol Genet 1997 Apr
PMID:A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A. 909 63


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