A Parathyroid Hormone-Related Protein Implicated in Malignant Hypercalcemia: Cloning and Expression

Suva, Larry J.; Winslow, Genine; Wettenhall, Richard E.H.; Hammonds, R. Glenn; Moseley, J. M.; Diefenbach-Jagger, H.; Rodda, Christine; Kemp, Bruce E.; Rodriguez, Henry; Chen, E. Y.; Hudson, Peter J.; Martin, T. J.; Wood, William I.

doi:10.1126/science.3616618

Cited by 1,247 publications

(516 citation statements)

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“…Although the PTHrP 1 -36 peptide is a propeptide (Suva et al, 1987;Juppner et al, 1991), the PTHrP 25 -34 peptide was included. With regard to the difference in amino acids, three amino acids were found to differ between the PTHrP 36 -44 peptide and PTH, and all of the amino acids were found to differ between the other three PTHrP peptides and PTH.…”

Section: Resultsmentioning

confidence: 99%

“…Parathyroid hormone-related protein has limited homology with PTH at its NH2 terminus, and can bind to the same receptor as PTH, resulting in similar biological activity (Suva et al, 1987;Juppner et al, 1991). Parathyroid hormone-related protein plays a variety of physiological roles, including calcium transport, keratinocyte differentiation, smooth muscle relaxation, and cartilage development (Philbrick et al, 1996).…”

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confidence: 99%

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Identification of parathyroid hormone-related protein-derived peptides immunogenic in human histocompatibility leukocyte antigen-A24+ prostate cancer patients

et al. 2004

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Parathyroid hormone-related protein (PTHrP) is a key factor in the development of bone metastases, which are a major barrier in treating prostate cancer patients. In this study, we attempted to identify PTHrP-derived peptides immunogenic in human histocompatibility leukocyte antigen (HLA)-A24 þ prostate cancer patients. Among four different PTHrP peptides carrying the HLA-A24 binding motif, both the PTHrP 36 -44 and PTHrP 102 -111 peptides efficiently induced peptide-specific cytotoxic T lymphocytes from peripheral blood mononuclear cells (PBMCs) of HLA-A24 þ prostate cancer patients. Peptide-stimulated PBMCs showed cytotoxicity against prostate cancer cells in an HLA-A24-restricted manner. Experiments using antibodies and cold inhibition targets confirmed that their cytotoxicity was dependent on PTHrP peptide-specific and CD8 þ T cells. Immunoglobulin G reactive to the PTHrP 102 -111 or PTHrP 110 -119 peptide was frequently detected in the plasma of prostate cancer patients, suggesting that the PTHrP 102 -111 peptide is able to elicit cellular and humoral immune responses in cancer patients. These results indicate that the PTHrP could be a promising target molecule for specific immunotherapy of HLA-A24 þ prostate cancer patients with metastases.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Identification of parathyroid hormone-related protein-derived peptides immunogenic in human histocompatibility leukocyte antigen-A24+ prostate cancer patients

et al. 2004

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“…(1) These peptides show high homology within their NH 2 -domain in the 1-34 amino acid (aa) sequence, by which they bind the same G-protein receptor (PTH-R1). (2,3) During fetal development PTHrP is produced by perichondral cells to adjust placental calcium levels and support the differentiation of endochondral cells to chondrocytes, (4,5) whereas after birth it concurs to development of mammary glands and lactation.…”

Section: Introductionmentioning

confidence: 99%

PTHrP Produced by Myeloma Plasma Cells Regulates Their Survival and Pro-Osteoclast Activity For Bone Disease Progression

Cafforio

Savonarola

Stucci

et al. 2013

Journal of Bone and Mineral Research

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To promote their survival and progression in the skeleton, osteotropic malignancies of breast, lung, and prostate produce parathyroid hormone-related protein (PTHrP), which induces hypercalcemia. PTHrP serum elevations have also been described in multiple myeloma (MM), although their role is not well defined. When we investigated MM cells from patients and cell lines, we found that PTHrP and its receptor (PTH-R1) are highly expressed, and that PTHrP is secreted both as a full-length molecule and as small subunits. Among these subunits, the mid-region, including the nuclear localization sequence (NLS), exerted a proliferative effect because it was accumulated in nuclei of MM cells surviving in starvation conditions. This was confirmed by increased transcription of several genes enrolled in proliferation and apoptosis control. PTHrP was also found to stimulate PTH-R1 in MM cells. PTH-R1's selective activation by the full-length PTHrP molecule or the NH 2 -terminal fragment resulted in a significant increase of intracellular Ca 2þ influx, cyclic adenosine monophosphate (cAMP) content, and expression of receptor activator of NF-kB ligand (RANKL) and monocyte chemoattractant protein-1 (MCP-1). Our data definitely clarify the role of PTHrP in MM. The PTHrP peptide is functionally secreted by malignant plasma cells and contributes to MM tumor biology and progression, both by intracrine maintenance of cell proliferation in stress conditions and by autocrine or paracrine stimulation of PTH-R1, which in turn reinforces the production of osteoclastogenic factors.

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“…1,2 Parathyroid hormonerelated protein was originally isolated, 3,4 cloned and sequenced 5,6 from tumors associated with hypercalcemia and has been identified in a variety of adult and fetal tissues. The human PTHrP gene is located on the short arm of chromosome 12 and consists of nine exons, of which two are present in all PTHrP transcripts: exon V, encoding the prepro region of the protein and exon VI, which encodes the mature protein up to residue 139.…”

Section: Introductionmentioning

confidence: 99%

Production of parathyroid hormone‐related protein in two new cell lines of renal cell carcinoma

et al. 2001

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Background: Hypercalcemia is the most common of all paraneoplastic syndromes and has been reported to appear in up to 20% of patients with renal cell carcinoma (RCC). Humoral hypercalcemia of malignancy is believed to be induced when parathyroid hormone-related protein (PTHrP) is excessively produced in cancer cells and impairs the homeostasis of serum calcium concentrations.Methods: Cancer cells were isolated from a surgical specimen and successfully cultured in a monolayer. The present study describes the establishment and characterization of new cell lines of RCC.Results: Two different cell lines, designated SMRC-1 and SMRC-3, were established from human RCC, each of which had been continuously secreting PTHrP in vitro. The patient from whom the SMRC-3 cells were obtained was shown to have elevated levels of PTHrP and resultant hypercalcemia. Cultured SMRC-1 was spindle-shaped in morphology. SMRC-3 had pleomorphic polygonal shapes and formed typical epithelial monolayers. Both cell types secreted intact, C-terminal PTHrP and interleukin-6 in the culture medium. Cellular messenger RNA of PTHrP was analyzed by reverse transcriptase-polymerase chain reaction. The SMRC-1 cells showed chromosome numbers ranging from 42 to 47 with consistent structural abnormalities of add(4)(q23~25) and add(6)(q13). The chromosomal analysis of SMRC-3 revealed a modal number of 95 with consistent structural abnormalities of add(1)(p36) and der(1;3)(q10;p10). Conclusions: These cell lines could be good models for investigating the mechanism of PTHrP production and the relationship between this hormone and hypercalcemia.

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A Parathyroid Hormone-Related Protein Implicated in Malignant Hypercalcemia: Cloning and Expression

Cited by 1,247 publications

References 30 publications

Identification of parathyroid hormone-related protein-derived peptides immunogenic in human histocompatibility leukocyte antigen-A24+ prostate cancer patients

Identification of parathyroid hormone-related protein-derived peptides immunogenic in human histocompatibility leukocyte antigen-A24+ prostate cancer patients

PTHrP Produced by Myeloma Plasma Cells Regulates Their Survival and Pro-Osteoclast Activity For Bone Disease Progression

Production of parathyroid hormone‐related protein in two new cell lines of renal cell carcinoma

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