Parathyroid hormone-related protein

Parathyroid hormone-related protein

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 carcinoma). However, it also has normal functions.

Functions

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 the 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 and lactation, possibly by regulating the mobilization and transfer of calcium to the milk, as well as placental transfer of calcium.

Hypercalcemia of Malignancy

PTHrP is related in function to the "normal" parathyroid hormone. When a tumor secretes PTHrP, this can lead to hypercalcemia. As this is sometimes the first sign of the malignancy, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon.

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). PTHR1 is responsible for most cases of humoral hypercalcemia of malignancy.

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. [cite web | title = Entrez Gene: PTHLH parathyroid hormone-like hormone| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5744| accessdate = ]

History

The protein was first isolated in 1988 by Broadus "et al". 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.

References

Further reading

* Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. "N Engl J Med" 1988;319:556-63. PMID 3043221.
* Miao D, Li J, Xue Y, Su H, Karaplis AC, Goltzman D. Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice. Endocrinology 2004;145:3554-62. PMID 15090463.PBB_Further_reading
citations =
*cite journal | author=Casey ML, MacDonald PC |title=The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta |journal=Hum. Reprod. |volume=11 Suppl 2 |issue= |pages= 62–82 |year= 1997 |pmid= 8982748 |doi=
*cite journal | author=Lam MH, Thomas RJ, Martin TJ, "et al." |title=Nuclear and nucleolar localization of parathyroid hormone-related protein |journal=Immunol. Cell Biol. |volume=78 |issue= 4 |pages= 395–402 |year= 2000 |pmid= 10947864| doi=10.1046/j.1440-1711.2000.00919.x
*cite journal | author=Fiaschi-Taesch NM, Stewart AF |title=Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences |journal=Endocrinology |volume=144 |issue= 2 |pages= 407–11 |year= 2003 |pmid= 12538599| doi=10.1210/en.2002-220818
*cite journal | author=Jans DA, Thomas RJ, Gillespie MT |title=Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles |journal=Vitam. Horm. |volume=66 |issue= |pages= 345–84 |year= 2003 |pmid= 12852260 |doi=
*cite journal | author=Maioli E, Fortino V, Pacini A |title=Parathyroid hormone-related protein in preeclampsia: a linkage between maternal and fetal failures |journal=Biol. Reprod. |volume=71 |issue= 6 |pages= 1779–84 |year= 2005 |pmid= 15286039 |doi= 10.1095/biolreprod.104.030932
*cite journal | author=Fenton AJ, Kemp BE, Kent GN, "et al." |title=A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts |journal=Endocrinology |volume=129 |issue= 4 |pages= 1762–8 |year= 1991 |pmid= 1915066 |doi=
*cite journal | author=Fenton AJ, Kemp BE, Hammonds RG, "et al." |title=A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP [107-111] |journal=Endocrinology |volume=129 |issue= 6 |pages= 3424–6 |year= 1991 |pmid= 1954916 |doi=
*cite journal | author=Moniz C, Burton PB, Malik AN, "et al." |title=Parathyroid hormone-related peptide in normal human fetal development |journal=J. Mol. Endocrinol. |volume=5 |issue= 3 |pages= 259–66 |year= 1991 |pmid= 2288637 |doi=
*cite journal | author=Hammonds RG, McKay P, Winslow GA, "et al." |title=Purification and characterization of recombinant human parathyroid hormone-related protein |journal=J. Biol. Chem. |volume=264 |issue= 25 |pages= 14806–11 |year= 1989 |pmid= 2549037 |doi=
*cite journal | author=Yasuda T, Banville D, Hendy GN, Goltzman D |title=Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects |journal=J. Biol. Chem. |volume=264 |issue= 13 |pages= 7720–5 |year= 1989 |pmid= 2708388 |doi=
*cite journal | author=Suva LJ, Mather KA, Gillespie MT, "et al." |title=Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP) |journal=Gene |volume=77 |issue= 1 |pages= 95–105 |year= 1989 |pmid= 2744490| doi=10.1016/0378-1119(89)90363-6
*cite journal | author=Mangin M, Webb AC, Dreyer BE, "et al." |title=Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 2 |pages= 597–601 |year= 1988 |pmid= 2829195| doi=10.1073/pnas.85.2.597
*cite journal | author=Moseley JM, Kubota M, Diefenbach-Jagger H, "et al." |title=Parathyroid hormone-related protein purified from a human lung cancer cell line |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 14 |pages= 5048–52 |year= 1987 |pmid= 2885845| doi=10.1073/pnas.84.14.5048
*cite journal | author=Mangin M, Ikeda K, Dreyer BE, Broadus AE |title=Isolation and characterization of the human parathyroid hormone-like peptide gene |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue= 7 |pages= 2408–12 |year= 1989 |pmid= 2928340| doi=10.1073/pnas.86.7.2408
*cite journal | author=Thiede MA, Strewler GJ, Nissenson RA, "et al." |title=Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 13 |pages= 4605–9 |year= 1988 |pmid= 3290897| doi=10.1073/pnas.85.13.4605
*cite journal | author=Suva LJ, Winslow GA, Wettenhall RE, "et al." |title=A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression |journal=Science |volume=237 |issue= 4817 |pages= 893–6 |year= 1987 |pmid= 3616618| doi=10.1126/science.3616618
*cite journal | author=Campos RV, Zhang L, Drucker DJ |title=Differential expression of RNA transcripts encoding unique carboxy-terminal sequences of human parathyroid hormone-related peptide |journal=Mol. Endocrinol. |volume=8 |issue= 12 |pages= 1656–66 |year= 1995 |pmid= 7708054 |doi=
*cite journal | author=Holick MF, Ray S, Chen TC, "et al." |title=A parathyroid hormone antagonist stimulates epidermal proliferation and hair growth in mice |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 17 |pages= 8014–6 |year= 1994 |pmid= 8058749| doi=10.1073/pnas.91.17.8014
*cite journal | author=Seitz PK, Cooper KM, Ives KL, "et al." |title=Parathyroid hormone-related peptide production and action in a myoepithelial cell line derived from normal human breast |journal=Endocrinology |volume=133 |issue= 3 |pages= 1116–24 |year= 1993 |pmid= 8396010| doi=10.1210/en.133.3.1116
*cite journal | author=Li H, Seitz PK, Selvanayagam P, "et al." |title=Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2) |journal=Endocrinology |volume=137 |issue= 6 |pages= 2367–74 |year= 1996 |pmid= 8641188| doi=10.1210/en.137.6.2367

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