Parathyroid Hormone-related Protein Gene Structure, Biosynthesis, Metabolism and Regulation
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2015 John P. Bilezikian, Robert Marcus, and Michael A. Levine Published by Elsevier Inc. All rights reserved.. After the discovery of parathyroid hormone-related protein (PTHrP) as the cause of the hypercalcemia of malignancy, it was found to be distributed widely in tissues, with many physiologic and pathologic roles as a paracrine effector. The involvement of PTHrP in cancer extended its contribution to include the ability of cancer cells to promote bone resorption and metastasize. PTHrP and PTH appear to have arisen from a common ancestral gene, but it is uncertain which came first. Both PTH and PTHrP are tracked in evolutionary time to fish, with evidence of both ligands in cartilagenous fish. The PTHrP gene (. PTHLH), with three promoters in the human gene and nine exons, has many simple variations, but the known structural and regulatory features of the gene are grossly conserved across multiple species. In their structural organizations, the chicken, mouse, and rat PTHLH genes share substantial homology with the human gene, although the mouse and rat genes are considerably simpler. Thus, the greater complexity of the human PTHLH gene appears to be a late evolutionary event. PTHrP has been found to have multiple activities within the protein sequence, beyond the amino-terminal domain, which shares with PTH action upon a common receptor. These additional domains include a nuclear localizing sequence, a specific nuclear transport system, and other domains associated with multiple biologic activities. The nuclear role(s), the susceptibility of PTHrP to endoproteolysis, together with the lability of PTHrP mRNA and the multiple splice forms, may be the result of evolutionary pressures that equip PTHrP to function as a paracrine agent, as it does in many tissues.
