Parathyroid Hormone-Related Protein: Evidence for Isoform- and Tissue-Specific Posttranslational Processing

Yang, Kyu Hyun; Ae, dePapp; Ne, Soifer; Be, Dreyer; Tl, Wu; Se, Porter; Bellantoni, M; Wj, Burtis; Insogna, Karl L.; Ae, Broadus

doi:10.1021/bi00189a054

Cited by 77 publications

(58 citation statements)

References 41 publications

(93 reference statements)

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“…16 In contrast, Yang et al have detected a C-terminal fragment that reacts with a PTHrP (109-138) antiserum in six distinct cell lines, including a renal carcinoma cell line and described this fragment as being a secretory form rather than a degradation product. 30 These findings in part seem to support our results in which the SMRC-1 cells probably secreted C-terminal fragments more than intact PTHrP. However, we could not conclude based upon these experiments whether the SMRC-1 cells directly secreted the C-terminal fragment, or whether the PTHrP were degraded to forms retaining the C-terminal region of the mature peptide.…”

Section: Discussionsupporting

confidence: 45%

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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Section: Discussionsupporting

confidence: 45%

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

et al. 2001

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“…The majority of early studies focused on either N-terminal PTHrP or the whole pro-hormone, with little interest in the other products of PTHrP. Studies focusing on midregion PTHrP identified it to be a secretory peptide, [20][21][22][23] with amino acids sequences of 38-94, 38-95 or 38-101. 24 PTHrP has also been associated with an intracrine role that is dependent on the bipartite nuclear localisation sequence (NLS) located in amino acids 88-106, 25,26 which following post-translation processing of PTHrP results in the NLS-(88-101) remaining within midregion PTHrP-(38-101) peptide.…”

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confidence: 99%

Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cells

Kumari

Robertson

Watson

2006

Intl Journal of Cancer

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Parathyroid-hormone related protein (PTHrP) is the primary factor in humoral hypercalcemia of malignancy and is highly secreted by breast cancers. The pro-hormone undergoes posttranslational processing and cleavage to give rise to mature secretory peptides, one of which is midregion PTHrP (38-94/95/101) containing a nuclear localisation sequence (NLS) in amino acids (87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106). The current study investigates whether the NLS in midregion PTHrP is important in breast cancer growth. PTHrP-(67-101), a midregion PTHrP fragment containing NLS-(87-101) significantly increased growth of MCF-7 and MDA-MB231 cells (126.3 and 121.3% of control respectively in serum conditions), independent of PTHR1 whereas PTHrP-(67-86), which lacks the NLS did not. Fluorescent-labelled PTHrP-(67-101) translocated to the nucleus, whereas PTHrP-(67-86) remained cytosolic and a scrambled(1NLS) peptide was not internalised. In comparison, no growth influence or uptake was seen in non-tumour breast cells (Hs578Bst). Increases in intracellular calcium mobilisation were observed in breast cancer cells stimulated with both PTHrP-(67-101) and PTHrP-(67-86) (EC 50 of 3.2 pM and 2.2 pM respectively for MCF-7 cells), whereas inositide turnover was not detected. Both nuclear uptake and calcium signalling were attenuated in the presence of EGTA, but not with U73122 or N-terminal PTHrP peptides. Our studies indicate that the NLS-containing midregion PTHrP peptide is dependent on both internalisation and nuclear translocation to induce growth in breast cancer cells. These findings highlight the importance of midregion PTHrP and its receptor in breast cancer growth and may provide potential targets for future therapeutic intervention. ' 2006 Wiley-Liss, Inc.Key words: PTHrP; breast cancer; NLS; calcium signalling; midregion PTHrP Parathyroid hormone-related protein (PTHrP) was first identified as a tumour-derived protein that was the primary factor in humoral hypercalcemia of malignancy (HHM). 1-3 The first 13 amino acids of PTHrP and parathyroid hormone (PTH) share significant homology 4,5 and it is this sequence which interacts with the parathyroid hormone receptor 1 (PTHR1). 6 As a result, tumour-derived PTHrP enters the circulation and activates PTHR1 in both the bone and kidney to induce PTH-like activity, the outcome of which is hypercalcaemia and osteoclast-mediated bone resorption. 1,2,7 PTHrP is expressed in breast epithelium and is associated with normal mammary gland function, cell growth and differentiation. [8][9][10][11][12] Studies using PTHrP knockout mice resulted in mammary epithelial cell degeneration, 13 emphasising the importance of PTHrP in breast growth. Breast cancers, in most cases, secrete high levels of PTHrP, [14][15][16] and as a result malignancy associated HHM is very common. The expression of PTHrP has also been reported to be higher in breast cancer skeletal metastases than in the primary tumour. 14,17,18 The role of PTHrP may therefore be biolog...

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“…Furthermore, by using rabbit anti-mid-region PTHrP, we specifically revealed a single band of approximately 7 kDa related to the mid-region, as described for other tumors. (9)(10)(11)(23)(24)(25) We also measured RNA levels of both PTHrP and PTH-R1 (Fig. 1D) in selected plasma cell samples, based on the highest cytometric expression.…”

Section: Calcium and Pthrp Serum Levelsmentioning

confidence: 99%

“…(22) The functional role of PTHrP fragments in human pathophysiology has been intensively investigated and their generation by posttranslational proteolysis of members of the subtilisin family, has been definitely assessed. (23)(24)(25) Tumors producing skeletal metastases are usually associated with high PTHrP activity that apparently correlates with poor prognosis in both breast and prostate cancers, (13) although a survival advantage has been unexpectedly described in female patients with lung adenocarcinoma and serum elevation of PTHrP. (26) Nevertheless, the role of PTHrP on cancer growth has been definitely confirmed by demonstrating that its suppression, by either neutralizing antibodies in MDA-MB-231 breast cancer cells or by antisense oligonucleotides in mouse models, restrains tumor progression, resulting in marked reduction of tumor size.…”

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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Parathyroid Hormone-Related Protein: Evidence for Isoform- and Tissue-Specific Posttranslational Processing

Cited by 77 publications

References 41 publications

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

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

Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cells

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

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