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Parathyroid hormone-related protein

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Parathyroid hormone-related protein

Parathyroid hormone-like hormone
PDB rendering based on 1bzg.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; BDE2; HHM; PLP; PTHR; PTHRP
External IDs GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt n/a
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Parathyroid hormone-related protein (or PTHrP) is a protein member of the parathyroid hormone family. It is occasionally secreted by cancer cells (breast cancer, certain types of lung cancer including squamous cell lung carcinoma). However, it also has normal functions.

Contents

  • Function 1
    • Tooth eruption 1.1
    • Mammary glands 1.2
    • Humoral hypercalcemia of malignancy 1.3
  • Genetics 2
  • Discovery 3
  • Interactions 4
  • References 5
  • Further reading 6

Function

PTHrP acts as an endocrine, autocrine, paracrine, and intracrine hormone. It regulates endochondral bone development by maintaining the endochondral growth plate at a constant width. It also regulates epithelial-mesenchymal interactions during the formation of the mammary glands.

Tooth eruption

PTHrP is critical in intraosseous phase of tooth eruption where it acts as a signalling molecule to stimulate local bone resorption. Without PTHrP, the bony crypt surrounding the tooth follicle will not resorb, and therefore the tooth will not erupt. In the context of tooth eruption, PTHrP is secreted by the cells of the Reduced Enamel Epithelium.

Mammary glands

It aids in normal mammary gland development.[1][2] It is necessary for maintenance of the mammary bud. Loss of PTHrP or its receptor causes the mammary bud cell fate to change back into epidermis. In lactation, it may regulate in conjunction with the calcium sensing receptor the mobilization and transfer of calcium to the milk, as well as placental transfer of calcium.

Humoral hypercalcemia of malignancy

PTHrP is related in function to the "normal" parathyroid hormone. When a tumor secretes PTHrP, this can lead to hypercalcemia.[3] As this is sometimes the first sign of the malignancy, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon. PTHR1 is responsible for most cases of humoral hypercalcemia of malignancy.

PTHrP shares the same N-terminal end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor (PTHR1). PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport.

However, PTHrP is less likely than PTH to stimulate 1,25-dihydroxyvitamin D production. Therefore, PTHrP does not increase intestinal calcium absorption.

Genetics

Four alternatively spliced transcript variants encoding two distinct isoforms have been observed. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, in-frame and downstream of the initiator AUG codon, to give rise to nuclear forms of this hormone.[4]

Discovery

The protein was first isolated in 1987 by T.J. Martin's team at the University of Melbourne. Miao et al. showed that disruption of the PTHrP gene in mice caused a lethal phenotype and distinct bone abnormalities, suggesting that PTHrP has a physiological function.

Interactions

Parathyroid hormone-related protein has been shown to interact with KPNB1[5][6] and Arrestin beta 1.[7]

References

  1. ^ Hens JR, Dann P, Zhang JP, Harris S, Robinson GW, Wysolmerski J (March 2007). "BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction". Development (Cambridge, England) 134 (6): 1221–30.  
  2. ^ Hens JR, Wysolmerski JJ (2005). "Key stages of mammary gland development: Molecular mechanisms involved in the formation of the embryonic mammary gland". Breast Cancer Research : BCR 7 (5): 220–4.  
  3. ^ Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF (September 1988). "Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide". The New England Journal of Medicine 319 (9): 556–63.  
  4. ^ "Entrez Gene: PTHLH parathyroid hormone-like hormone". 
  5. ^ Cingolani, Gino; Bednenko Janna; Gillespie Matthew T; Gerace Larry (Dec 2002). "Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta". Mol. Cell (United States) 10 (6): 1345–53.  
  6. ^ Lam, M H; Hu W; Xiao C Y; Gillespie M T; Jans D A (Mar 2001). "Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein". Biochem. Biophys. Res. Commun. (United States) 282 (2): 629–34.  
  7. ^ Conlan, Lindus A; Martin T John; Gillespie Matthew T (Sep 2002). "The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B". FEBS Lett. (Netherlands) 527 (1–3): 71–5.  

Further reading

  • Miao D, Li J, Xue Y, Su H, Karaplis AC, Goltzman D (August 2004). "Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice". Endocrinology 145 (8): 3554–62.  
  • Casey ML, MacDonald PC (1997). "The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta". Hum. Reprod. 11 Suppl 2: 62–82.  
  • Lam MH, Thomas RJ, Martin TJ, et al. (2000). "Nuclear and nucleolar localization of parathyroid hormone-related protein". Immunol. Cell Biol. 78 (4): 395–402.  
  • Fiaschi-Taesch NM, Stewart AF (2003). "Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences". Endocrinology 144 (2): 407–11.  
  • Jans DA, Thomas RJ, Gillespie MT (2003). "Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles". Vitam. Horm. Vitamins & Hormones 66: 345–84.  
  • Maioli E, Fortino V, Pacini A (2005). "Parathyroid hormone-related protein in preeclampsia: a linkage between maternal and fetal failures". Biol. Reprod. 71 (6): 1779–84.  
  • Fenton AJ, Kemp BE, Kent GN, et al. (1991). "A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts". Endocrinology 129 (4): 1762–8.  
  • Fenton AJ, Kemp BE, Hammonds RG, et al. (1991). "A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP[107-111]". Endocrinology 129 (6): 3424–6.  
  • Moniz C, Burton PB, Malik AN, et al. (1991). "Parathyroid hormone-related peptide in normal human fetal development". J. Mol. Endocrinol. 5 (3): 259–66.  
  • Hammonds RG, McKay P, Winslow GA, et al. (1989). "Purification and characterization of recombinant human parathyroid hormone-related protein". J. Biol. Chem. 264 (25): 14806–11.  
  • Yasuda T, Banville D, Hendy GN, Goltzman D (1989). "Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects". J. Biol. Chem. 264 (13): 7720–5.  
  • Suva LJ, Mather KA, Gillespie MT, et al. (1989). "Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP)". Gene 77 (1): 95–105.  
  • Mangin M, Webb AC, Dreyer BE, et al. (1988). "Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy". Proc. Natl. Acad. Sci. U.S.A. 85 (2): 597–601.  
  • Moseley JM, Kubota M, Diefenbach-Jagger H, et al. (1987). "Parathyroid hormone-related protein purified from a human lung cancer cell line". Proc. Natl. Acad. Sci. U.S.A. 84 (14): 5048–52.  
  • Mangin M, Ikeda K, Dreyer BE, Broadus AE (1989). "Isolation and characterization of the human parathyroid hormone-like peptide gene". Proc. Natl. Acad. Sci. U.S.A. 86 (7): 2408–12.  
  • Thiede MA, Strewler GJ, Nissenson RA, et al. (1988). "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. U.S.A. 85 (13): 4605–9.  
  • Suva LJ, Winslow GA, Wettenhall RE, et al. (1987). "A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression". Science 237 (4817): 893–6.  
  • Campos RV, Zhang L, Drucker DJ (1995). "Differential expression of RNA transcripts encoding unique carboxy-terminal sequences of human parathyroid hormone-related peptide". Mol. Endocrinol. 8 (12): 1656–66.  
  • Holick MF, Ray S, Chen TC, et al. (1994). "A parathyroid hormone antagonist stimulates epidermal proliferation and hair growth in mice". Proc. Natl. Acad. Sci. U.S.A. 91 (17): 8014–6.  
  • Seitz PK, Cooper KM, Ives KL, et al. (1993). "Parathyroid hormone-related peptide production and action in a myoepithelial cell line derived from normal human breast". Endocrinology 133 (3): 1116–24.  
  • Li H, Seitz PK, Selvanayagam P, et al. (1996). "Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2)". Endocrinology 137 (6): 2367–74.  

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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