Parathyroid hormone-related protein

Parathyroid hormone-related protein (or PTHrP) is a protein member of the parathyroid hormone family secreted by mesenchymal stem cells. 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 in bone, tooth, vascular and other tissues.

PTHLH
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPTHLH, BDE2, HHM, PLP, PTHR, PTHRP, parathyroid hormone-like hormone, parathyroid hormone like hormone
External IDsOMIM: 168470 MGI: 97800 HomoloGene: 2113 GeneCards: PTHLH
Orthologs
SpeciesHumanMouse
Entrez

5744

19227

Ensembl

ENSG00000087494

ENSMUSG00000048776

UniProt

P12272

P22858

RefSeq (mRNA)

NM_002820
NM_198964
NM_198965
NM_198966

NM_008970

RefSeq (protein)

NP_002811
NP_945315
NP_945316
NP_945317

n/a

Location (UCSC)Chr 12: 27.96 – 27.97 MbChr 6: 147.15 – 147.17 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6] 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.[7] 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. PTHrP lacks the normal feedback inhibition as PTH.[8]

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.[9]

Discovery

In 1986, researchers at Montreal's McGill University purified proteins with "PTH-like" bioactivity that were extracted from Leydig cell tumor and human squamous cell carcinoma, demonstrating that the purified "PTH-like" peptides (i.e., PTHrP) extracted from malignancies associated with hypercalcemia could be used in in-vitro and in-vivo assays.[10] 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. Researchers at McGill University in Montreal showed circulating concentrations of PTHrP were involved in malignancy and hyperparathyroidism.[11] In 1991, some of the same researchers from McGill University demonstrated that growth factors may accutely stimulate PTHrP mRNA levels and release; in contrast, 1,25(OH)2D3 inhibited those responses, suggesting that part of these effects could be explained at the gene transcription level.[12]

Role in Cancer

PTHrP is thought to play an emerging role in cancer[13][14] and has been discussed as a potential therapy target from resulting studies in breast cancer[15][16] and pancreatic cancer.[17][18][19] PTHrP has been demonstrated to be a molecular driver of epithelial to mesenchymal transition (EMT).[20][21]

Breast Cancer

PTHrP was shown to be a driver of breast cancer initiation, progression, and metastasis in 2011.[22]

Triple-Negative Breast Cancer

PTHrP was studied in a cohort of 314 Triple-Negative Breast Cancer (TNBC) patients and was shown to be a statistically significant independent prognostic factor for CNS- progression-free-survival and was the only statistically significant prognostic factor for overall survival (OS) of low-clinical risk node-negative patients who hadn't received adjuvant chemotherapy.[23] A later study in animal models demonstrated that anti-PTHrP antibodies could block TNBC expansion in bone through epithelial to mesenchymal transition (EMT) reversal, suggesting that PTHrP is a potential therapeutic target for TNBC-derived bone lesions.[24]

Pancreatic Cancer

PTHrP was also shown to be a driver of pancreatic cancer growth and metastasis.[25]

Melanoma

In animal studies, anti-PTHrP antibodies were shown to reduce tumors size by 80% and significantly increase survival for mice over 8 months, providing direct evidence of PTHrP's role in melanoma invasion and metastasis.[26]

Interactions

Parathyroid hormone-related protein has been shown to interact with KPNB1[27][28] and Arrestin beta 1.[29]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000087494 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000048776 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. 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.
  7. 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.
  8. Stewart, Andrew F. (2005-01-27). "Clinical practice. Hypercalcemia associated with cancer". The New England Journal of Medicine. 352 (4): 373–379. doi:10.1056/NEJMcp042806. ISSN 1533-4406. PMID 15673803.
  9. "Entrez Gene: PTHLH parathyroid hormone-like hormone".
  10. Rabbani, Shafaat A.; Mitchell, Jane; Roy, Denis R.; Kremer, Richard; Bennett, Hugh P. J.; Goltzman, David (March 1986). "Purification of Peptides with Parathyroid Hormone-Like Bioactivity from Human and Rat Malignancies Associated with Hypercalcemia". Endocrinology. 118 (3): 1200–1210. doi:10.1210/endo-118-3-1200. PMID 3948772.
  11. Henderson, Janet E.; Shustik, Chaim; Kremer, Richard; Rabbani, Shafaat A.; Hendy, Geoffrey N.; Goltzman, David; Hendy, Geoffrey N.; Goltzman, David (February 1990). "Circulating concentrations of parathyroid hormone-like peptide in malignancy and in hyperparathyroidism". Journal of Bone and Mineral Research. 5 (2): 105–113. doi:10.1002/jbmr.5650050203. PMID 2316398. S2CID 28259300.
  12. Kremer, R.; Karaplis, A. C.; Henderson, J.; Gulliver, W.; Banville, D.; Hendy, G. N.; Goltzman, D. (1 March 1991). "Regulation of parathyroid hormone-like peptide in cultured normal human keratinocytes. Effect of growth factors and 1,25 dihydroxyvitamin D3 on gene expression and secretion". The Journal of Clinical Investigation. 87 (3): 884–893. doi:10.1172/JCI115094. PMC 329878. PMID 1999499.
  13. Zhang, Rui; Li, Jiarong; Assaker, Gloria; Camirand, Anne; Sabri, Siham; Karaplis, Andrew C.; Kremer, Richard (2019). "Parathyroid Hormone-Related Protein (PTHrP): An Emerging Target in Cancer Progression and Metastasis". Human Cell Transformation. Advances in Experimental Medicine and Biology. 1164: 161–178. doi:10.1007/978-3-030-22254-3_13. ISBN 978-3-030-22253-6. PMID 31576548. S2CID 203639665.
  14. Kremer, Richard; Li, Jiarong; Camirand, Anne; Karaplis, Andrew C. (2011). "Parathyroid Hormone Related Protein (PTHrP) in Tumor Progression". Human Cell Transformation. Advances in Experimental Medicine and Biology. 720: 145–160. doi:10.1007/978-1-4614-0254-1_12. ISBN 978-1-4614-0253-4. PMID 21901625.
  15. https://www.mcgill.ca/newsroom/channels/news/new-target-identified-stop-spread-breast-cancer-211888
  16. Li, Jiarong; Karaplis, Andrew C.; Huang, Dao C.; Siegel, Peter M.; Camirand, Anne; Yang, Xian Fang; Muller, William J.; Kremer, Richard (1 December 2011). "PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target". The Journal of Clinical Investigation. 121 (12): 4655–4669. doi:10.1172/JCI46134. PMC 3225988. PMID 22056386.
  17. Pitarresi, Jason R.; Norgard, Robert J.; Chiarella, Anna M.; Suzuki, Kensuke; Bakir, Basil; Sahu, Varun; Li, Jinyang; Zhao, Jun; Marchand, Benoît; Wengyn, Maximilian D.; Hsieh, Antony; Kim, Il-Kyu; Zhang, Amy; Sellin, Karine; Lee, Vivian; Takano, Shigetsugu; Miyahara, Yoji; Ohtsuka, Masayuki; Maitra, Anirban; Notta, Faiyaz; Kremer, Richard; Stanger, Ben Z.; Rustgi, Anil K. (1 July 2021). "PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability". Cancer Discovery. 11 (7): 1774–1791. doi:10.1158/2159-8290.CD-20-1098. PMC 8292165. PMID 33589425.
  18. "Scientists Reveal a New Therapeutic Vulnerability in Pancreatic Cancer". 11 March 2021.
  19. "Mouse Study Reveals New Therapeutic Target in Pancreatic Cancer". 2 July 2021.
  20. Li, Jiarong; Camirand, Anne; Zakikhani, Mahvash; Sellin, Karine; Guo, Yubo; Luan, XiaoRui; Mihalcioiu, Catalin; Kremer, Richard (29 November 2021). "Parathyroid hormone‐related protein inhibition blocks triple‐negative breast cancer expansion in bone through epithelial to mesenchymal transition reversal". JBMR Plus: jbm4.10587. doi:10.1002/jbm4.10587. S2CID 244734532.
  21. Pitarresi, Jason R.; Norgard, Robert J.; Chiarella, Anna M.; Suzuki, Kensuke; Bakir, Basil; Sahu, Varun; Li, Jinyang; Zhao, Jun; Marchand, Benoît; Wengyn, Maximilian D.; Hsieh, Antony; Kim, Il-Kyu; Zhang, Amy; Sellin, Karine; Lee, Vivian; Takano, Shigetsugu; Miyahara, Yoji; Ohtsuka, Masayuki; Maitra, Anirban; Notta, Faiyaz; Kremer, Richard; Stanger, Ben Z.; Rustgi, Anil K. (1 July 2021). "PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability". Cancer Discovery. 11 (7): 1774–1791. doi:10.1158/2159-8290.CD-20-1098. PMC 8292165. PMID 33589425.
  22. Li, Jiarong; Karaplis, Andrew C.; Huang, Dao C.; Siegel, Peter M.; Camirand, Anne; Yang, Xian Fang; Muller, William J.; Kremer, Richard (1 December 2011). "PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target". The Journal of Clinical Investigation. 121 (12): 4655–4669. doi:10.1172/JCI46134. PMC 3225988. PMID 22056386.
  23. Assaker, Gloria; Camirand, Anne; Abdulkarim, Bassam; Omeroglu, Atilla; Deschenes, Jean; Joseph, Kurian; Noman, Abu Shadat Mohammod; Ramana Kumar, Agnihotram V; Kremer, Richard; Sabri, Siham (29 August 2019). "PTHrP, A Biomarker for CNS Metastasis in Triple-Negative Breast Cancer and Selection for Adjuvant Chemotherapy in Node-Negative Disease". JNCI Cancer Spectrum. 4 (1): pkz063. doi:10.1093/jncics/pkz063. PMC 7050156. PMID 32296756.
  24. Li, Jiarong; Camirand, Anne; Zakikhani, Mahvash; Sellin, Karine; Guo, Yubo; Luan, XiaoRui; Mihalcioiu, Catalin; Kremer, Richard (29 November 2021). "Parathyroid hormone‐related protein inhibition blocks triple‐negative breast cancer expansion in bone through epithelial to mesenchymal transition reversal". JBMR Plus: jbm4.10587. doi:10.1002/jbm4.10587. S2CID 244734532.
  25. Pitarresi, Jason R.; Norgard, Robert J.; Chiarella, Anna M.; Suzuki, Kensuke; Bakir, Basil; Sahu, Varun; Li, Jinyang; Zhao, Jun; Marchand, Benoît; Wengyn, Maximilian D.; Hsieh, Antony; Kim, Il-Kyu; Zhang, Amy; Sellin, Karine; Lee, Vivian; Takano, Shigetsugu; Miyahara, Yoji; Ohtsuka, Masayuki; Maitra, Anirban; Notta, Faiyaz; Kremer, Richard; Stanger, Ben Z.; Rustgi, Anil K. (1 July 2021). "PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability". Cancer Discovery. 11 (7): 1774–1791. doi:10.1158/2159-8290.CD-20-1098. PMC 8292165. PMID 33589425.
  26. Huang, Dao Chao; Yang, Xian Fang; Ochietti, Benoît; Fadhil, Ibtihal; Camirand, Anne; Kremer, Richard (1 October 2014). "Parathyroid Hormone-Related Protein: Potential Therapeutic Target for Melanoma Invasion and Metastasis". Endocrinology. 155 (10): 3739–3749. doi:10.1210/en.2013-1803. PMID 25051432.
  27. 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.
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  29. 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. S2CID 83640616.

Further reading

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