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.
Since the elucidation of the structures of the three human PRHrP isoforms in 1987, information has rapidly accured which indicates that the role of PTHrP in normal physiology will prove to be crucial as well as exceedingly complex. The importance of the role of PTHrP in normal physiology is underscored by its broad tissue expression, by its intense evolutionary conservation, by its extremely early expression after fertilization of the ovum, and by the lethal consequences of PTHrP gene disruption. The complexity of the role of PTHrP in normal physiology increases almost monthly. This complexity is reflected in the broad tissue distribution of the peptide, its complex transcriptional regulation and mRNA instability motifs, and its multiple transcripts and isoforms. It is now clear that additional complexity exists at the level of posttranslational processing. Expression of the PTHrP gene leads to the tissue-specific processing and secretion of an increasingly complex family of derivative peptides, each with its own repertoire of cognate receptors, signal transduction pathways, and physiological consequences. Further elucidation of the posttranslational processing pathways and mechanisms can be anticipated in the coming years, coupled with a corresponding elucidation of multiple PTHrP receptors, their specific signal transduction pathways, and their unique physiological roles. The role of PTHrP in causing HHM is now clearly established. Work in the coming decade will focus on the normal physiological roles played by PTHrP.
Parathyroid hormone-related protein (PTHrP) is initially translated as a preprohormone which is posttranslationally processed to yield a family of mature secretory forms. Most attention has focused on the aminoterminal portion of the molecule which is homologous to parathyroid hormone. It is clear, however, that a midregion species of PTHrP is posttranslationally cleaved from the highly conserved mid-region of PTHrP, and that the amino terminus of this peptide is Ala 38 . The purposes of the current study were three: 1) to confirm that Arg 37 immediately preceding Ala 38 serves as a posttranslational processing site in the PTHrP precursor, 2) to determine the carboxyl terminus of the mid-region secretory species of PTHrP, and 3) to synthesize this authentic mid-region secretory form of PTHrP and determine whether it is biologically active. The results indicate that: 1) Arg 37 is indeed a processing site in the PTHrP precursor; 2) three distinct mid-region PTHrP species are generated by posttranslational processing, PTHrP(38 -94)amide, PTHrP(38 -95), and most likely, PTHrP(38 -101); and 3) synthetic mid-region PTHrP(38 -94)amide is active in four different biological systems. These studies confirm the finding that PTHrP is a prohormone. More importantly, they define a novel, biologically active highly conserved mid-region secretory form of PTHrP.Parathyroid hormone-related protein (PTHrP) 1 was initially discovered through its structural and functional homology with parathyroid hormone (for a review, see Refs.
A data broker sells market segmentations to a producer with private cost who sells a product to a unit mass of consumers. This paper characterizes the revenue-maximizing mechanisms for the data broker. Every optimal mechanism induces quasi-perfect price discrimination. All the consumers with values above a cost-dependent cutoff buy by paying their values while the rest of consumers do not buy. The characterization implies that market outcomes remain unchanged even if the data broker becomes more powerful—either by gaining the ability to sell access to consumers or by becoming a retailer who purchases the product and sells to the consumers exclusively. (JEL D42, D82, D83, L81, M31)
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