Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets

Abstract

The cloning of the so-called 'parathyroid hormone-related protein' (PTHrP) in 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate gene. Second, with the exception of a short N-terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly-hormone which comprises a family of distinct peptide hormones arising from post-translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. PTHrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identification of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo-vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.

Figure 1

Structure of parathyroid hormone-related protein (PTHrP) gene in human, rat and mouse, as compared to the less complex human PTH gene. Key features of PTHrP genes are (a) the use of two (rat and mouse) or three different promoters (in human), indicated by arrows; the use of alternative splicing (splice options shown by bent lines connecting exons) which in human gives rise to three different coding-region protein isoforms of 139, 141 and 173 aminoacids in human or to a single protein of 141 aminoacids in rat and 139 aminoacids in mouse. Exons are shown as hatched boxes (5′-non coding exons), dotted boxes (mature coding region) or open boxes (3′-untranslated region). Like in growth factor or cytokine genes, the 3′-untranslated regions of the various PTHrP mRNAS contain multiple copies of an AUUUA motif, responsible for rapid degradation and short half-life. Moreover, the presence of TATA boxes and GC sequences in the promoting region suggests complex regulation of expression. In human, the PTHrP gene (15 kb) is located on the short arm of chromosome 12, while PTH gene is located on an analogous region on the short arm of chromosome 11; both chromosomes most likely arising from a common ancestral gene.

Figure 2

The three initial PTHrP isoforms arising from alternative splicing as shown in Figure 1, the posttranslational processing at multibasic endoproteolytic sites (multi-K/R), and the amino-terminal, mid-region and carboxy-terminal mature secretory forms of PTHrP, as they are understood at present. PTHrP(1-36) is the mature PTHrP species exhibiting PTH-like properties, not only in bone and kidney, but also in a number of other systems, including the cardiovascular system. This region contains the 1 – 13 region in which 8 aminoacid are homologous to the analogous region in PTH. Note also the bipartite nuclear/nucleolar targeted sequence (NTS, also referred to as “NLS”) in the 88 – 106 region (see text).