The role of DNA methylation in the expression of parathyroid hormone-related protein in humoral hypercalcemia of malignancy

1993 ◽  
Vol 21 (1) ◽  
pp. 11S-11S ◽  
Author(s):  
ROSALIND H. GANDERTON ◽  
ROGER S. J. BRIGGS
Keyword(s):  
Dna Methylation ◽  
Parathyroid Hormone ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Hypercalcemia Of Malignancy ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein

Defining the roles of parathyroid hormone-related protein in normal physiology

1996 ◽  
Vol 76 (1) ◽  
pp. 127-173 ◽  
Author(s):  
W. M. Philbrick ◽  
J. J. Wysolmerski ◽  
S. Galbraith ◽  
E. Holt ◽  
J. J. Orloff ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Fetal Life ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Physiological Functions ◽  
Hypercalcemia Of Malignancy ◽  
Normal Tissues ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Differentiation And Proliferation

Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which causes the common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since the identification of the peptide in 1982 and the cloning of the cDNA in 1987, it has become clear that PTHrP is a prohormone that is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only in cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalcemia of malignancy in which PTHrP plays the role of a classical "endocrine" hormone, under normal circumstances PTHrP plays predominantly paracrine and/or autocrine roles. These apparent physiological functions are also complex and appear to include 1) regulation of smooth muscle (vascular, intestinal, uterine, bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct, mammary gland) calcium transport, and 3) regulation of tissue and organ development, differentiation, and proliferation. In this review, the discovery of PTHrP, the structure of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.

Parathyroid Hormone-Related Protein: Structure, Function, and Measurement

1992 ◽  
Vol 38 (11) ◽  
pp. 2171-2183 ◽  
Author(s):  
W J Burtis
Keyword(s):  
Parathyroid Hormone ◽  
Amino Acid ◽  
Amino Acid Sequences ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Hypercalcemia Of Malignancy ◽  
Physiological Importance ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Order Of Magnitude

Abstract Parathyroid hormone-related protein (PTHRP) is a 139- to 173-amino-acid protein with N-terminal homology to parathyroid hormone (PTH). Initially isolated from tumors from patients with humoral hypercalcemia of malignancy, PTHRP appears to be of far more widespread physiological importance. Its complex gene is expressed in a surprising diversity of tissues. The primary amino acid sequences of both the PTH-like and non-PTH-like regions of the protein are highly conserved across species. In addition to classical and nonclassical PTH-like activities of the N-terminal region, other biological functions have been ascribed, including augmentation of calcium transport by midregion PTHRP and potent inhibition of bone resorption by a C-terminal peptide. There is emerging evidence that the protein undergoes extensive processing, including glycosylation and defined proteolytic cleavages. Several region-specific immunoassays are now capable of measuring circulating concentrations of PTHRP in patients with humoral hypercalcemia of malignancy. Molar concentrations of different regions may differ by more than an order of magnitude, reflecting diversity in processing and (or) metabolism. By analyzing the results of these assays, taking into account the specificities of known endoproteases, one can hypothesize about some of the endoproteolytic cleavages that occur in PTHRP metabolism. Clinically, selected PTHRP assays can be very helpful in diagnosing PTHRP-mediated hypercalcemia, but are not yet sufficiently sensitive to accurately measure normal concentrations of the protein.

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