Parathyroid hormone-related protein
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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.
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.
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.
It aids in normal mammary gland development. 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. 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.
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.
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.
Parathyroid hormone-related protein has been shown to interact with KPNB1 and Arrestin beta 1.
- Analogs used as pharmaceutical drugs
- ↑ 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. 134 (6): 1221–30. doi:10.1242/dev.000182. PMID 17301089.
- ↑ 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. 7 (5): 220–4. doi:10.1186/bcr1306. PMC 1242158. PMID 16168142.
- ↑ 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. doi:10.1056/NEJM198809013190906. PMID 3043221.
- ↑ "Entrez Gene: PTHLH parathyroid hormone-like hormone".
- ↑ Cingolani G, Bednenko J, Gillespie MT, Gerace L (December 2002). "Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta". Molecular Cell. 10 (6): 1345–53. doi:10.1016/S1097-2765(02)00727-X. PMID 12504010.
- ↑ Lam MH, Hu W, Xiao CY, Gillespie MT, Jans DA (March 2001). "Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein". Biochemical and Biophysical Research Communications. 282 (2): 629–34. doi:10.1006/bbrc.2001.4607. PMID 11401507.
- ↑ Conlan LA, Martin TJ, Gillespie MT (September 2002). "The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B". FEBS Letters. 527 (1–3): 71–5. doi:10.1016/S0014-5793(02)03164-2. PMID 12220636.
- 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. doi:10.1210/en.2003-1695. PMID 15090463.
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- Lam MH, Thomas RJ, Martin TJ, Gillespie MT, Jans DA (August 2000). "Nuclear and nucleolar localization of parathyroid hormone-related protein". Immunology and Cell Biology. 78 (4): 395–402. doi:10.1046/j.1440-1711.2000.00919.x. PMID 10947864.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.