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Historical Perspective and Evolutionary Origins of Parathyroid Hormone-Related Protein

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Abstract

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 its actions driving many physiologic and pathologic conditions. Its involvement in cancer extended to a contribution to the ability of cancer cells to promote bone resorption and establish as metastases. It was found to have multiple activities within the sequence, including a nuclear localizing sequence and a specific nuclear transport system. PTHrP and parathyroid hormone (PTH) appear to have arisen from a common ancestral gene and the comparative endocrinology and genomics studies focused on finding where the two genes appeared. PTHrP has been identified in bony and cartilaginous fish in the same tissues as in humans, indicating that PTHrP has fundamental and basic physiological roles in all vertebrates. PTHrP has been localized in fish neoplasms suggesting that PTHrP’s role in tumor formation is a conserved role from at least fish to humans. Interestingly, PTH has been identified in both bony and cartilaginous fish even though they lack a parathyroid gland and indicate that PTH’s evolutionary history is much longer too. So the point where PTHrP and PTH were duplicated is still unknown. A comparison among the analogous human, mouse, chicken, xenopus, and fugu sequences of the PTHrP gene demonstrates elements of conservation. When coupled with human Encode data and knowledge of interspecies gene structure, it offers rudimentary insights into function and underwrites hypotheses on physiology.

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Abbreviations

PTHrP:

Parathyroid hormone-related protein

PTH:

Parathyroid hormone

HHM:

Humoral hypercalcemia of malignancy

PTHLH :

Parathyroid hormone like hormone (the gene encodes the PTHrP protein in humans)

Pthlh :

Parathyroid hormone like hormone (the gene encodes the PTHrP protein in rodents)

PTH1R:

Parathyroid hormone 1 receptor

pthrp :

Parathyroid hormone-related protein (the gene that encodes the Pthrp protein in fish and amphibia)

VMA:

Vertebrate Multiz Alignment

UTR:

Untranslated region

CcN:

CK2-cdc2-NLS motif

NLS:

Nuclear localization sequence

NFT2:

Nuclear transport factor 2

References

  1. Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall RE, Kemp BE, Suva LJ, et al. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci USA. 1987;84(14):5048–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, et al. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987;237(4817):893–6.

    CAS  PubMed  Google Scholar 

  3. Albright F. Case records of the Massachusetts general Hospital—case 39061. N Engl J Med. 1941;1941:789–96.

    Google Scholar 

  4. Berson SA, Yalow RS. Parathyroid hormone in plasma in adenomatous hyperparathyroidism, uremia, and bronchogenic carcinoma. Science. 1966;154(3751):907–9.

    CAS  PubMed  Google Scholar 

  5. Lafferty FW. Pseudohyperparathyroidism. Medicine (Baltimore). 1966;45(3):247–60.

    CAS  Google Scholar 

  6. Roof BS, Carpenter B, Fink DJ, Gordan GS. Some thoughts on the nature of ectopic parathyroid hormones. Am J Med. 1971;50(5):686–91.

    CAS  PubMed  Google Scholar 

  7. Riggs BL, Arnaud CD, Reynolds JC, Smith LH. Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer. J Clin Investig. 1971;50(10):2079–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Benson RC Jr, Riggs BL, Pickard BM, Arnaud CD. Immunoreactive forms of circulating parathyroid hormone in primary and ectopic hyperparathyroidism. J Clin Investig. 1974;54(1):175–81.

    PubMed Central  PubMed  Google Scholar 

  9. Melick RA, Martin TJ, Hicks JD. Parathyroid hormone production and malignancy. Br Med J. 1972;2(5807):204–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Powell D, Singer FR, Murray TM, Minkin C, Potts JT Jr. Nonparathyroid humoral hypercalcemia in patients with neoplastic diseases. N Engl J Med. 1973;289(4):176–81.

    CAS  PubMed  Google Scholar 

  11. Martin TJ, Atkins D. Biochemical regulators of bone resorption and their significance in cancer. Essays Med Biochem. 1979;4:49–82.

    CAS  Google Scholar 

  12. Stewart AF, Horst R, Deftos LJ, Cadman EC, Lang R, Broadus AE. Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med. 1980;303(24):1377–83.

    CAS  PubMed  Google Scholar 

  13. Rude RK, Sharp CF Jr, Fredericks RS, Oldham SB, Elbaum N, Link J, et al. Urinary and nephrogenous adenosine 3’,5’-monophosphate in the hypercalcemia of malignancy. J Clin Endocrinol Metab. 1981;52(4):765–71.

    CAS  PubMed  Google Scholar 

  14. Kukreja SC, Shemerdiak WP, Lad TE, Johnson PA. Elevated nephrogenous cyclic AMP with normal serum parathyroid hormone levels in patients with lung cancer. J Clin Endocrinol Metab. 1980;51(1):167–9.

    CAS  PubMed  Google Scholar 

  15. Atkins D, Hunt NH, Ingleton PM, Martin TJ. Rat osteogenic sarcoma cells: isolation and effects of hormones on the production of cyclic AMP and cyclic GMP. Endocrinology. 1977;101(2):555–61.

    CAS  PubMed  Google Scholar 

  16. Partridge NC, Alcorn D, Michelangeli VP, Kemp BE, Ryan GB, Martin TJ. Functional properties of hormonally responsive cultured normal and malignant rat osteoblastic cells. Endocrinology. 1981;108(1):213–9.

    CAS  PubMed  Google Scholar 

  17. Majeska RJ, Rodan SB, Rodan GA. Parathyroid hormone-responsive clonal cell lines from rat osteosarcoma. Endocrinology. 1980;107(5):1494–503.

    CAS  PubMed  Google Scholar 

  18. Stewart AF, Insogna KL, Goltzman D, Broadus AE. Identification of adenylate cyclase-stimulating activity and cytochemical glucose-6-phosphate dehydrogenase-stimulating activity in extracts of tumors from patients with humoral hypercalcemia of malignancy. Proc Natl Acad Sci USA. 1983;80(5):1454–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Strewler GJ, Williams RD, Nissenson RA. Human renal carcinoma cells produce hypercalcemia in the nude mouse and a novel protein recognized by parathyroid hormone receptors. J Clin Investig. 1983;71(3):769–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Rodan SB, Insogna KL, Vignery AM, Stewart AF, Broadus AE, D’Souza SM, et al. Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells. J Clin Investig. 1983;72(4):1511–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Goltzman D, Stewart AF, Broadus AE. Malignancy-associated hypercalcemia: evaluation with a cytochemical bioassay for parathyroid hormone. J Clin Endocrinol Metab. 1981;53(5):899–904.

    CAS  PubMed  Google Scholar 

  22. Stewart AF, Wu T, Goumas D, Burtis WJ, Broadus AE. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase-stimulating proteins: identification of parathyroid hormone-like and parathyroid hormone-unlike domains. Biochem Biophys Res Commun. 1987;146(2):672–8.

    CAS  PubMed  Google Scholar 

  23. Strewler GJ, Stern PH, Jacobs JW, Eveloff J, Klein RF, Leung SC, et al. Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. J Clin Investig. 1987;80(6):1803–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Mangin M, Ikeda K, Broadus AE. Structure of the mouse gene encoding parathyroid hormone-related peptide. Gene. 1990;95(2):195–202.

    CAS  PubMed  Google Scholar 

  25. Kemp BE, Moseley JM, Rodda CP, Ebeling PR, Wettenhall RE, Stapleton D, et al. Parathyroid hormone-related protein of malignancy: active synthetic fragments. Science. 1987;238(4833):1568–70.

    CAS  PubMed  Google Scholar 

  26. Moseley JM, Gillespie MT. Parathyroid hormone-related protein. Crit Rev Clin Lab Sci. 1995;32(3):299–343.

    CAS  PubMed  Google Scholar 

  27. Moseley JM, Hayman JA, Danks JA, Alcorn D, Grill V, Southby J, et al. Immunohistochemical detection of parathyroid hormone-related protein in human fetal epithelia. J Clin Endocr Metab. 1991;73(3):478–84.

    CAS  PubMed  Google Scholar 

  28. Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 1994;8(3):277–89.

    CAS  PubMed  Google Scholar 

  29. Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC. Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation. J Cell Biol. 1994;126(6):1611–23.

    CAS  PubMed  Google Scholar 

  30. Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science. 1996;273(5275):663–6.

    CAS  PubMed  Google Scholar 

  31. Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science. 1996;273(5275):613–22.

    CAS  PubMed  Google Scholar 

  32. Amizuka N, Karaplis AC, Henderson JE, Warshawsky H, Lipman ML, Matsuki Y, et al. Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. Dev Biol. 1996;175(1):166–76.

    CAS  PubMed  Google Scholar 

  33. Miao D, He B, Jiang Y, Kobayashi T, Soroceanu MA, Zhao J, et al. Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Investig. 2005;115(9):2402–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Charbon GA. A rapid and selective vasodialtor effect of parathyroid hormone. Eur J Pharmacol. 1968;3(3):275–8.

    CAS  PubMed  Google Scholar 

  35. Charbon GA, Hulstaert PF. Augmentation of arterial hepatic and renal flow by extracted and synthetic parathyroid hormone. Endocrinology. 1974;95(2):621–6.

    CAS  PubMed  Google Scholar 

  36. Wang HH, Drugge ED, Yen YC, Blumenthal MR, Pang PK. Effects of synthetic parathyroid hormone on hemodynamics and regional blood flows. Eur J Pharmacol. 1984;97(3–4):209–15.

    CAS  PubMed  Google Scholar 

  37. Mok LL, Nickols GA, Thompson JC, Cooper CW. Parathyroid hormone as a smooth muscle relaxant. Endocr Rev. 1989;10(4):420–36.

    CAS  PubMed  Google Scholar 

  38. Pirola CJ, Wang HM, Kamyar A, Wu S, Enomoto H, Sharifi B, et al. Angiotensin II regulates parathyroid hormone-related protein expression in cultured rat aortic smooth muscle cells through transcriptional and post-transcriptional mechanisms. J Biol Chem. 1993;268(3):1987–94.

    CAS  PubMed  Google Scholar 

  39. Massfelder T, Helwig JJ, Stewart AF. Parathyroid hormone-related protein as a cardiovascular regulatory peptide. Endocrinology. 1996;137(8):3151–3.

    CAS  PubMed  Google Scholar 

  40. Winquist RJ, Baskin EP, Vlasuk GP. Synthetic tumor-derived human hypercalcemic factor exhibits parathyroid hormone-like vasorelaxation in renal arteries. Biochem Biophys Res Commun. 1987;149(1):227–32.

    CAS  PubMed  Google Scholar 

  41. Shew RL, Yee JA, Kliewer DB, Keflemariam YJ, McNeill DL. Parathyroid hormone-related protein inhibits stimulated uterine contraction in vitro. J Bone Miner Res. 1991;6(9):955–9.

    CAS  PubMed  Google Scholar 

  42. Philbrick WM, Wysolmerski JJ, Galbraith S, Holt E, Orloff JJ, Yang KH, et al. Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev. 1996;76(1):127–73.

    CAS  PubMed  Google Scholar 

  43. Martin TJ, Moseley JM, Williams ED. Parathyroid hormone-related protein: hormone and cytokine. J Endocrinol. 1997;154(Suppl):S23–37.

    CAS  PubMed  Google Scholar 

  44. Aarts MM, Rix A, Guo J, Bringhurst R, Henderson JE. The nucleolar targeting signal (NTS) of parathyroid hormone related protein mediates endocytosis and nucleolar translocation. J Bone Miner Res. 1999;14(9):1493–503.

    CAS  PubMed  Google Scholar 

  45. Henderson JE, Amizuka N, Warshawsky H, Biasotto D, Lanske BM, Goltzman D, et al. Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. Mol Cell Biol. 1995;15(8):4064–75.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Okano K, Pirola CJ, Wang HM, Forrester JS, Fagin JA, Clemens TL. Involvement of cell cycle and mitogen-activated pathways in induction of parathyroid hormone-related protein gene expression in rat aortic smooth muscle cells. Endocrinology. 1995;136(4):1782–9.

    CAS  PubMed  Google Scholar 

  47. Lam MH, Olsen SL, Rankin WA, Ho PW, Martin TJ, Gillespie MT, et al. PTHrP and cell division: expression and localization of PTHrP in a keratinocyte cell line (HaCaT) during the cell cycle. J Cell Physiol. 1997;173(3):433–46.

    CAS  PubMed  Google Scholar 

  48. Nguyen M, He B, Karaplis A. Nuclear forms of parathyroid hormone-related peptide are translated from non-AUG start sites downstream from the initiator methionine. Endocrinology. 2001;142(2):694–703.

    CAS  PubMed  Google Scholar 

  49. Massfelder T, Dann P, Wu TL, Vasavada R, Helwig JJ, Stewart AF. Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: a critical role for nuclear targeting. Proc Natl Acad Sci USA. 1997;94(25):13630–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Jans DA. The regulation of protein transport to the nucleus by phosphorylation. Biochem J. 1995;311(Pt 3):705–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Lam MH, Thomas RJ, Loveland KL, Schilders S, Gu M, Martin TJ, et al. Nuclear transport of parathyroid hormone (PTH)-related protein is dependent on microtubules. Mol Endocrinol. 2002;16(2):390–401.

    CAS  PubMed  Google Scholar 

  52. Cingolani G, Bednenko J, Gillespie MT, Gerace L. Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta. Mol Cell. 2002;10(6):1345–53.

    CAS  PubMed  Google Scholar 

  53. Amizuka N, Fukushi-Irie M, Sasaki T, Oda K, Ozawa H. Inefficient function of the signal sequence of PTHrP for targeting into the secretory pathway. Biochem Biophys Res Commun. 2000;273(2):621–9.

    CAS  PubMed  Google Scholar 

  54. Lam MH, House CM, Tiganis T, Mitchelhill KI, Sarcevic B, Cures A, et al. Phosphorylation at the cyclin-dependent kinases site (Thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization. J Biol Chem. 1999;274(26):18559–66.

    CAS  PubMed  Google Scholar 

  55. Jans DA, Briggs LJ, Gustin SE, Jans P, Ford S, Young IG. The cytokine interleukin-5 (IL-5) effects cotransport of its receptor subunits to the nucleus in vitro. FEBS Lett. 1997;410(2–3):368–72.

    CAS  PubMed  Google Scholar 

  56. Liu Y, Berendsen AD, Jia S, Lotinun S, Baron R, Ferrara N, et al. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Investig. 2012;122(9):3101–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Watson PH, Fraher LJ, Natale BV, Kisiel M, Hendy GN, Hodsman AB. Nuclear localization of the type 1 parathyroid hormone/parathyroid hormone-related peptide receptor in MC3T3-E1 cells: association with serum-induced cell proliferation. Bone. 2000;26(3):221–5.

    CAS  PubMed  Google Scholar 

  58. Watson PH, Fraher LJ, Hendy GN, Chung UI, Kisiel M, Natale BV, et al. Nuclear localization of the type 1 PTH/PTHrP receptor in rat tissues. J Bone Miner Res. 2000;15(6):1033–44.

    CAS  PubMed  Google Scholar 

  59. Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991;254(5034):1024–6.

    CAS  PubMed  Google Scholar 

  60. Rodda CP, Kubota M, Heath JA, Ebeling PR, Moseley JM, Care AD, et al. Evidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy. J Endocrinol. 1988;117(2):261–71.

    CAS  PubMed  Google Scholar 

  61. Abbas SK, Pickard DW, Rodda CP, Heath JA, Hammonds RG, Wood WI, et al. Stimulation of ovine placental calcium transport by purified natural and recombinant parathyroid hormone-related protein (PTHrP) preparations. Q J Exp Physiol. 1989;74(4):549–52.

    CAS  PubMed  Google Scholar 

  62. Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM. Parathyroid hormone-related peptide (PTHrP) regulates fetal–placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci USA. 1996;93(26):15233–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Fenton AJ, Martin TJ, Nicholson GC. Long-term culture of disaggregated rat osteoclasts: inhibition of bone resorption and reduction of osteoclast-like cell number by calcitonin and PTHrP[107–139]. J Cell Physiol. 1993;155(1):1–7.

    CAS  PubMed  Google Scholar 

  64. Cornish J, Callon KE, Nicholson GC, Reid IR. Parathyroid hormone-related protein-(107–139) inhibits bone resorption in vivo. Endocrinology. 1997;138(3):1299–304.

    CAS  PubMed  Google Scholar 

  65. Cornish J, Callon KE, Lin C, Xiao C, Moseley JM, Reid IR. Stimulation of osteoblast proliferation by C-terminal fragments of parathyroid hormone-related protein. J Bone Miner Res. 1999;14(6):915–22.

    CAS  PubMed  Google Scholar 

  66. de Gortazar AR, Alonso V, Alvarez-Arroyo MV, Esbrit P. Transient exposure to PTHrP (107–139) exerts anabolic effects through vascular endothelial growth factor receptor 2 in human osteoblastic cells in vitro. Calcif Tissue Int. 2006;79(5):360–9.

    CAS  PubMed  Google Scholar 

  67. Alonso V, de Gortazar AR, Ardura JA, Andrade-Zapata I, Alvarez-Arroyo MV, Esbrit P. Parathyroid hormone-related protein (107–139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor-2. J Cell Physiol. 2008;217(3):717–27.

    CAS  PubMed  Google Scholar 

  68. Portal-Nunez S, Lozano D, de Castro LF, de Gortazar AR, Nogues X, Esbrit P. Alterations of the Wnt/beta-catenin pathway and its target genes for the N- and C-terminal domains of parathyroid hormone-related protein in bone from diabetic mice. FEBS Lett. 2010;584(14):3095–100.

    CAS  PubMed  Google Scholar 

  69. Valin A, Guillen C, Esbrit P. C-terminal parathyroid hormone-related protein (PTHrP) (107–139) stimulates intracellular Ca(2+) through a receptor different from the type 1 PTH/PTHrP receptor in osteoblastic osteosarcoma UMR 106 cells. Endocrinology. 2001;142(7):2752–9.

    CAS  PubMed  Google Scholar 

  70. Divieti P, Inomata N, Chapin K, Singh R, Juppner H, Bringhurst FR. Receptors for the carboxyl-terminal region of pth(1–84) are highly expressed in osteocytic cells. Endocrinology. 2001;142(2):916–25.

    CAS  PubMed  Google Scholar 

  71. Miao D, Su H, He B, Gao J, Xia Q, Zhu M, et al. Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein. Proc Natl Acad Sci USA. 2008;105(51):20309–14.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Toribio RE, Brown HA, Novince CM, Marlow B, Hernon K, Lanigan LG, et al. The midregion, nuclear localization sequence, and C terminus of PTHrP regulate skeletal development, hematopoiesis, and survival in mice. FASEB J. 2010;24(6):1947–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Burtis WJ, Fodero JP, Gaich G, Debeyssey M, Stewart AF. Preliminary characterization of circulating amino- and carboxy-terminal fragments of parathyroid hormone-related peptide in humoral hypercalcemia of malignancy. J Clin Endocrinol Metab. 1992;75(4):1110–4.

    CAS  PubMed  Google Scholar 

  74. Bruns ME, Ferguson JE 2nd, Bruns DE, Burton DW, Brandt DW, Juppner H, et al. Expression of parathyroid hormone-related peptide and its receptor messenger ribonucleic acid in human amnion and chorion-decidua: implications for secretion and function. Am J Obstet Gynecol. 1995;173(3 Pt 1):739–46.

    CAS  PubMed  Google Scholar 

  75. Orloff JJ, Reddy D, de Papp AE, Yang KH, Soifer NE, Stewart AF. Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev. 1994;15(1):40–60.

    CAS  PubMed  Google Scholar 

  76. Fiaschi-Taesch NM, Stewart AF. Minireview: parathyroid hormone-related protein as an intracrine factor–trafficking mechanisms and functional consequences. Endocrinology. 2003;144(2):407–11.

    CAS  PubMed  Google Scholar 

  77. Mangin M, Ikeda K, Dreyer BE, Milstone L, Broadus AE. Two distinct tumor-derived, parathyroid hormone-like peptides result from alternative ribonucleic acid splicing. Mol Endocrinol. 1988;2(11):1049–55.

    CAS  PubMed  Google Scholar 

  78. Thiede MA, Strewler GJ, Nissenson RA, Rosenblatt M, Rodan GA. Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene. Proc Natl Acad Sci USA. 1988;85(13):4605–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Yasuda T, Banville D, Hendy GN, Goltzman D. Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects. J Biol Chem. 1989;264(13):7720–5.

    CAS  PubMed  Google Scholar 

  80. Mangin M, Ikeda K, Dreyer BE, Broadus AE. Isolation and characterization of the human parathyroid hormone-like peptide gene. Proc Natl Acad Sci USA. 1989;86(7):2408–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Suva LJ, Mather KA, Gillespie MT, Webb GC, Ng KW, Winslow GA, et al. Structure of the 5’ flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP). Gene. 1989;77(1):95–105.

    CAS  PubMed  Google Scholar 

  82. Comings D. Evidence for ancient tetraploidy and conservation of linkage groups in mammalian chromosomes. Nature. 1972;238:455–7.

    CAS  PubMed  Google Scholar 

  83. Danks JA, Trivett MK. Endocrinology and evolution: lessons from comparative endocrinology. In: Wass JAH, editor. Oxford textbook of endocrinology and diabetes. 1 ed. Oxford: Oxford University Press; 2002. p. 9–13.

    Google Scholar 

  84. Vasavada RC, Wysolmerski JJ, Broadus AE, Philbrick WM. Identification and characterization of a GC-rich promoter of the human parathyroid hormone-related peptide gene. Mol Endocrinol. 1993;7(2):273–82.

    CAS  PubMed  Google Scholar 

  85. Zajac JD, Callaghan J, Eldridge C, Diefenbach-Jagger H, Suva LJ, Hudson P, et al. Production of parathyroid hormone-related protein by a rat parathyroid cell line. Mol Cell Endocrinol. 1989;67(1):107–12.

    CAS  PubMed  Google Scholar 

  86. Ikeda K, Mangin M, Dreyer BE, Webb AC, Posillico JT, Stewart AF, et al. Identification of transcripts encoding a parathyroid hormone-like peptide in messenger RNAs from a variety of human and animal tumors associated with humoral hypercalcemia of malignancy. J Clin Investig. 1988;81(6):2010–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Butkus A, Roche PJ, Fernley RT, Haralambidis J, Penschow JD, Ryan GB, et al. Purification and cloning of a corpuscles of Stannius protein from Anguilla australis. Mol Cell Endocrinol. 1987;54(2–3):123–33.

    CAS  PubMed  Google Scholar 

  88. Chang ACM, Janosi J, Hulsbeek M, Dejong D, Jeffrey KJ, Noble JR, et al. A novel human cDNA highly homologous to the fish hormone stanniocalcin. Mol Cell Endocrinol. 1995;112(2):241–7.

    CAS  PubMed  Google Scholar 

  89. Ingleton PM, Danks JA. Parathyroid hormone-related protein in the saccus vasculosus of fishes. In: Dacke C, Danks J, Caple I, Flik G, editors. The comparative endocrinology of calcium regulation. Bristol: Journal of Endocrinology Ltd; 1996. p. 103–5.

    Google Scholar 

  90. Danks JA, Hubbard PC, Balment RJ, Ingleton PM, Martin TJ. Parathyroid hormone-related protein localization in tissues of freshwater and salt-acclimated flounder. J Bone Miner Res. 1996;11:435.

    Google Scholar 

  91. Danks JA, Devlin AJ, Ho PMW, Diefenbachjagger H, Power DM, Canario A, et al. Parathyroid hormone-related protein is a factor in normal fish pituitary. Gen Comp Endocrinol. 1993;92(2):201–12.

    CAS  PubMed  Google Scholar 

  92. Parsons JA, Gray, D, Rafferty B, Zanelli JM. Evidence for a hypercalcaemic factor in the fish pituitary immunologically related to mammalian parathyroid hormone. In: Copp DH, Talmage RV, editors. Endocrinology of calcium metabolism. Proceedings of the 6th parathyroid conference, Vancouver, Canada, June 12–17, 1977. Amsterdam: Excerpta Medica; 1979. p. 111–4.

  93. Kaneko T, Pang PK. Immunocytochemical detection of parathyroid hormone-like substance in the goldfish brain and pituitary gland. Gen Comp Endocrinol. 1987;68(1):147–52.

    CAS  PubMed  Google Scholar 

  94. Fraser RA, Kaneko T, Pang PK, Harvey S. Hypo- and hypercalcemic peptides in fish pituitary glands. Am J Physiol. 1991;260(3 Pt 2):R622–6.

    CAS  PubMed  Google Scholar 

  95. Trivett MK, Officer RA, Clement JG, Walker TI, Joss JM, Ingleton PM, et al. Parathyroid hormone-related protein (PTHrP) in cartilaginous and bony fish tissues. J Exp Zool. 1999;284(5):541–8.

    CAS  PubMed  Google Scholar 

  96. Trivett MK, Potter IC, Power G, Zhou H, Macmillan DL, Martin TJ, et al. Parathyroid hormone-related protein production in the lamprey Geotria australis: developmental and evolutionary perspectives. Dev Genes Evol. 2005;215(11):553–63.

    CAS  PubMed  Google Scholar 

  97. Trivett MK, Walker TI, Clement JG, Ho PM, Martin TJ, Danks JA. Effects of water temperature and salinity on parathyroid hormone-related protein in the circulation and tissues of elasmobranchs. Comp Biochem Physiol B: Biochem Mol Biol. 2001;129(2–3):327–36.

    CAS  Google Scholar 

  98. Danks JA, Trivett MK, Power DM, Canario AV, Martin TJ, Ingleton PM. Parathyroid hormone-related protein in lower vertebrates. Clin Exp Pharmacol Physiol. 1998;25(9):750–2.

    CAS  PubMed  Google Scholar 

  99. Danks JA, Ho PM, Notini AJ, Katsis F, Hoffmann P, Kemp BE, et al. Identification of a parathyroid hormone in the fish Fugu rubripes. J Bone Miner Res. 2003;18(7):1326–31.

    CAS  PubMed  Google Scholar 

  100. Canario AVM, Rotllant J, Fuentes J, Guerreiro PM, Teodosio HR, Power DM, et al. Novel bioactive parathyroid hormone and related peptides in teleost fish. FEBS Lett. 2006;580(1):291–9.

    CAS  PubMed  Google Scholar 

  101. Pinheiro PLC, Cardoso JCR, Gomes AS, Fuentes J, Power DM, Canario AVM. Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken. BMC Evol Biol. 2010;10:373. doi:10.1186/1471-2148-10-373.

  102. Ohno S. Evolution by gene duplication. Berlin: Springer; 1970.

    Google Scholar 

  103. Lynch M, Force A. The probability of duplicate gene preservation by subfunctionalization. Genetics. 2000;154(1):459–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Liu Y, Ibrahim AS, Tay BH, Richardson SJ, Bell J, Walker TI, et al. Parathyroid hormone gene family in a cartilaginous fish, the elephant shark (Callorhinchus milii). J Bone Miner Res. 2010;25(12):2613–23.

    PubMed  Google Scholar 

  105. Venkatesh B, Kirkness EF, Loh YH, Halpern AL, Lee AP, Johnson J, et al. Survey sequencing and comparative analysis of the elephant shark (Callorhinchus milii) genome. PLoS Biol. 2007;5(4):e101.

    PubMed Central  PubMed  Google Scholar 

  106. Yan YL, Bhattacharya P, He XJ, Ponugoti B, Marquardt B, Layman J, et al. Duplicated zebrafish co-orthologs of parathyroid hormone-related peptide (PTHrP, Pthlh) play different roles in craniofacial skeletogenesis. J Endocrinol. 2012;214(3):421–35.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12(6):996–1006.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Siepel A, Pollard KS, Haussler D. New methods for detecting lineage-specific selection. Res Comput Mol Biol Lect Notes Comput Sci. 2006;3909:190–205.

    Google Scholar 

  109. Murphy WJ, Eizirik E, O’Brien SJ, Madsen O, Scally M, Douady CJ, et al. Resolution of the early placental mammal radiation using Bayesian phylogenetics. Science. 2001;294(5550):2348–51.

    CAS  PubMed  Google Scholar 

  110. Rosenbloom KR, Sloan CA, Malladi VS, Dreszer TR, Learned K, Kirkup VM, et al. ENCODE data in the UCSC genome browser: year 5 update. Nucleic Acids Res. 2013;41(Database issue):D56–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Rubin DA, Hellman P, Zon LI, Lobb CJ, Bergwitz C, Juppner H. A G protein-coupled receptor from zebrafish is activated by human parathyroid hormone and not by human or teleost parathyroid hormone-related peptide. Implications for the evolutionary conservation of calcium-regulating peptide hormones. J Biol Chem. 1999;274(33):23035–42.

    CAS  PubMed  Google Scholar 

  112. Rubin DA, Juppner H. Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide. J Biol Chem. 1999;274(40):28185–90.

    CAS  PubMed  Google Scholar 

  113. Usdin TB, Hoare SR, Wang T, Mezey E, Kowalak JA. TIP39: a new neuropeptide and PTH2-receptor agonist from hypothalamus. Nat Neurosci. 1999;2(11):941–3.

    CAS  PubMed  Google Scholar 

  114. Danks JA, Ebeling PR, Hayman J, Chou ST, Moseley JM, Dunlop J, et al. Parathyroid hormone-related protein—immunohistochemical localization in cancers and in normal skin. J Bone Miner Res. 1989;4(2):273–8.

    CAS  PubMed  Google Scholar 

  115. Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, et al. Immunohistochemical localization of parathyroid hormone-related protein in human breast-cancer. Cancer Res. 1990;50(23):7710–6.

    CAS  PubMed  Google Scholar 

  116. Trivett MK, Harshbarger JC, Martin TJ, Danks JA. Is parathyroid hormone-related protein a marker of neoplasia in all vertebrates? J Bone Miner Res. 2000;15:S321.

    Google Scholar 

  117. Danks JA, McHale JC, Martin TJ, Ingleton PM. Parathyroid hormone-related protein in tissues of the emerging frog (Rana temporaria): immunohistochemistry and in situ hybridisation. J Anat. 1997;190(Pt 2):229–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Bergwitz C, Klein P, Kohno H, Forman SA, Lee K, Rubin D, et al. Identification functional characterization, and developmental expression of two nonallelic parathyroid hormone (PTH)/PTH-related peptide receptor isoforms in Xenopus laevis (daudin). Endocrinology. 1998;139(2):723–32.

    CAS  PubMed  Google Scholar 

  119. Pinheiro PLC, Cardoso JCR, Power DM, Canario AVM. Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken. BMC Evol Biol. 2012;12:110.

    Google Scholar 

  120. Gay CV. Avian bone resorption at a cellular level. CRC Crit Rev Poult Biol. 1988;1:197–210.

    Google Scholar 

  121. Kenny AD, Dacke CG. Hypercalcemic response to parathyroid-hormone in Japanese-quail. J Endocrinol. 1974;62(1):15–23.

    CAS  PubMed  Google Scholar 

  122. Dacke CG, Shaw AJ. Studies of the rapid effects of parathyroid-hormone and prostaglandins on Ca-45 uptake into chick and rat bone invivo. J Endocrinol. 1987;115(3):369–77.

    CAS  PubMed  Google Scholar 

  123. Thiede MA, Harm SC, Mckee RL, Grasser WA, Duong LT, Leach RM. Expression of the parathyroid hormone-related protein gene in the avian oviduct—potential role as a local modulator of vascular smooth-muscle tension and shell gland motility during the egg-laying cycle. Endocrinology. 1991;129(4):1958–66.

    CAS  PubMed  Google Scholar 

  124. Khosla S, Demay M, Pines M, Hurwitz S, Potts JT Jr, Kronenberg HM. Nucleotide sequence of cloned cDNAs encoding chicken preproparathyroid hormone. J Bone Miner Res. 1988;3(6):689–98.

    CAS  PubMed  Google Scholar 

  125. Schermer DT, Chan SDH, Bruce R, Nissenson RA, Wood WI, Strewler GJ. Chicken parathyroid hormone-related protein and its expression during embryologic development. J Bone Miner Res. 1991;6(2):149–55.

    CAS  PubMed  Google Scholar 

  126. Thiede MA, Rutledge SJ. Nucleotide-sequence of a parathyroid hormone-related peptide expressed by the 10 day chicken-embryo. Nucleic Acids Res. 1990;18(10):3062.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Zhao Q, Brauer PR, Xiao L, McGuire MH, Yee JA. Expression of parathyroid hormone-related peptide (PthrP) and its receptor (PTH1R) during the histogenesis of cartilage and bone in the chicken mandibular process. J Anat. 2002;201(2):137–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Medill NJ, Praul CA, Ford BC, Leach RM. Parathyroid hormone-related peptide expression in the epiphyseal growth plate of the juvenile chicken: evidence for the origin of the parathyroid hormone-related peptide found in the epiphyseal growth plate. J Cell Biochem. 2001;80(4):504–11.

    CAS  PubMed  Google Scholar 

  129. Bhattacharya P, Yan YL, Postlethwait J, Rubin DA. Evolution of the vertebrate pth2 (tip39) gene family and the regulation of PTH type 2 receptor (pth2r) and its endogenous ligand pth2 by hedgehog signaling in zebrafish development. J Endocrinol. 2011;211(2):187–200.

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Mehta TK, Ravi V, Yamasaki S, Lee AP, Lian MM, Tay BH, et al. Evidence for at least six Hox clusters in the Japanese lamprey (Lethenteron japonicum). Proc Natl Acad Sci USA. 2013;110(40):16044–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Danks JA, D’Souza DG, Gunn HJ, Milley KM, Richardson SJ. Evolution of the parathyroid hormone family and skeletal formation pathways. Gen Comp Endocrinol. 2011;170(1):79–91.

    CAS  PubMed  Google Scholar 

  132. Hull K, Marler R, Harvey S. Neural calcitropic peptides: immunoreactive characterization in fish and invertebrates. Neurosci Lett. 2006;404(1–2):15–9.

    CAS  PubMed  Google Scholar 

  133. Kamesh N, Aradhyam GK, Manoj N. The repertoire of G protein-coupled receptors in the sea squirt Ciona intestinalis. BMC Evol Biol. 2008;8:129.

    CAS  PubMed Central  PubMed  Google Scholar 

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Conflict of Interest

Janine A. Danks, Adam N. Freeman and T. John Martin declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Medical Sciences, RMIT University, PO Box 71, Bundoora, VIC, 3083, Australia

    Janine A. Danks

  2. Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC, 3081, Australia

    Janine A. Danks

  3. Department of Surgery, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, 3051, Australia

    Adam N. Freeman

  4. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Parkville, VIC, 3052, Australia

    Adam N. Freeman

  5. Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, 3051, Australia

    T. John Martin

  6. St Vincent’s Institute of Medical Research, Fitzroy, VIC, 3051, Australia

    T. John Martin

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  1. Janine A. Danks
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Correspondence to Janine A. Danks.

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Danks, J.A., Freeman, A.N. & Martin, T.J. Historical Perspective and Evolutionary Origins of Parathyroid Hormone-Related Protein. Clinic Rev Bone Miner Metab 12, 104–118 (2014). https://doi.org/10.1007/s12018-014-9163-8

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