Frontiers reviewParathyroid hormone-related protein and lung biology
Introduction
Parathyroid hormone-related protein (PTHrP) was named for its similarity in primary and secondary structure with the amino terminal portion of parathyroid hormone (PTH) (Kemp et al., 1987). The two proteins share some effects but serve different purposes. In contrast to the global endocrine action of PTH, PTHrP generally functions in a local paracrine or autocrine manner. Furthermore, the most important biologic consequences of the protein relate to cell growth and apoptosis, calcium transport, and smooth muscle relaxation, not to serum calcium homeostasis (Goltzman et al., 1989). The effects are mediated at several sites. PTHrP is a secretory protein (Deftos et al., 1993) and it exerts paracrine or autocrine effects at cell surface receptors. In addition, it can enter the nucleus to mediate changes in function or growth, actions known as intracrine effects. The effects of PTHrP have been studied in a wide variety of organs, including bone, kidney, prostate, skin, heart, brain and recently lung. PTHrP is an oncofetal protein in some tissues because its expression is restricted to the period of fetal development or to malignancy. However, many normal tissues produce PTHrP throughout life. The molecule is expressed in fetal lung, adult lung, and lung cancer, and has roles in development, normal pulmonary physiology, and the pathophysiology of lung injury and lung cancer. This review article will summarize pertinent background information regarding the molecular biology of PTHrP and discuss the importance of the molecule in pulmonary biology.
Section snippets
PTHrP gene
The human PTHrP gene displays a complex organization that enables expression to be regulated through alternative messenger RNA (mRNA) splicing and multiple promoters. The sequence spans more than 15 kilobases and consists of seven exons, six introns, three separate promoters, and multiple 3′-non-coding regions (Yang and Stewart, 1996). The gene codes for three separate isoforms in humans through production of different 3′ transcripts: PTHrP 1–141, a truncated PTHrP 1–139 version, and PTHrP
Pulmonary PTHrP and PTH-1R expression
PTHrP mRNA and protein are expressed in bronchial epithelium of the developing lung, beginning at days 14–16 of gestation in rats (term 21–23 d) and 7–12 weeks in humans (term 38–40 weeks) (Moniz et al., 1990, Senior et al., 1990, Campos et al., 1991, Moseley et al., 1991). Levels peak shortly before birth. Expression is largely restricted to the epithelial cells, while PTH-1R is found in the adjacent mesenchymal tissues (Lee et al., 1995). This hand-in-glove distribution between ligand and
PTHrP in adult lung
Type II cells make PTHrP in lungs of adult rats and rabbits, just as in fetal lung. Immunoassay, immunohistochemistry and in situ hybridization studies demonstrate PTHrP protein and mRNA in the parenchyma and protein in bronchoalveolar lavage liquid (BAL) (Hastings et al., 1994, 1996, 2002b). Cultured adult rat type II cells make PTHrP, but immunoreactive PTHrP or PTHrP mRNA have not been observed in type I cells, endothelial cells or fibroblasts. Freshly isolated alveolar macrophages and
PTHrP in lung injury
Various types of lung injury can result in damage to the alveolar epithelium, particularly to the alveolar type I epithelial cells that form the thin epithelial portion of the blood–gas barrier. With type I cells injured or missing, proteinaceous fluid and inflammatory cells can flood across the denuded epithelial basement membrane, leading to abnormalities in gas exchange and lung mechanics (Bachofen and Weibel, 1977). If the barrier is repaired, the injury and resulting effects can be
PTHrP expression
PTHrP was originally discovered in BEN cells, a squamous cell lung carcinoma line (Moseley et al., 1987), and PTHrP expression is a common characteristic of lung cancer cells of all histologic types (Brandt et al., 1991). Over half (estimates between 55–95%) of all lung cancer cell lines and human lung tumors express PTHrP (Asa et al., 1990, Brandt et al., 1991, Kitazawa et al., 1991, Davidson et al., 1996, Nishigaki et al., 1999). Expression may be more common in squamous cell carcinoma and
Conclusion
PTHrP is a versatile regulatory molecule in the field of pulmonary biology with potential roles in lung development, normal alveolar physiology, recovery from lung injury, regulation of cell growth and death, and the pathophysiology of lung cancer (Fig. 9). The protein may be a useful marker for assessing lung maturity, predicting risk of injury, evaluating type II cell function, detecting lung cancer, or following response to chemotherapy. Given its role in these processes, future work might
Acknowledgements
This work was supported by a VA Merit Review Award, NIEHS grant ES09227, the California Tobacco-Related Disease Research Program Grant Number 10RT-0161, and a grant from the Flight Attendants Medical Research Institute.
References (114)
- et al.
Parathyroid hormone-related protein interacts with RNA
J. Biol. Chem.
(1999) - et al.
Parathyroid hormone-related protein promotes quiescence and survival of serum-deprived chondrocytes by inhibiting rRNA synthesis
J. Biol. Chem.
(2001) - et al.
Inefficient function of the signal sequence of PTHrP for targeting into the secretory pathway
Biochem. Biophys. Res. Commun.
(2000) - et al.
The parathyroid hormone-related protein (PTHrP) gene preferentially utilizes a GC-rich promoter and the PTHrP 1–139 coding pathways in normal human amnion
Biochem. Biophys. Res. Commun.
(1992) - et al.
Parathyroid hormone-related peptide can function as an autocrine growth factor in human renal cell carcinoma
Biochem. Biophys. Res. Commun.
(1990) - et al.
Parathyroid hormone-related peptide can regulate the growth of human lung cancer cells, and may form part of an autocrine TGF-α loop
FEBS Lett.
(1992) - et al.
Alternative splicing: multiple control mechanisms and involvement in human disease
Trends Genet.
(2002) - et al.
Cloning of the cDNA for sea bream (Sparus aurata) parathyroid hormone-related protein
Gen. Comp. Endocrinol.
(2000) - et al.
Parathyroid hormone-like peptide: molecular characterization and biological properties
Trends Endocrinol. Metab.
(1989) - et al.
Parathyroid hormone-related protein and lung injury after pulmonary thromboendarterectomy
Regul. Pept.
(2001)
Role of parathyroid hormone-related protein in lung cancer cell survival
Chest
Establishment of two human small cell lung cancer cell lines: The evidence of accelerated production of parathyroid hormone-related protein with tumor progression
Cancer Lett.
Proteolysis of ProPTHrP(1–141) by “prohormone thiol protease” at multibasic residues generates PTHrP-related peptides: implications for PTHrP peptide production in lung cancer cells
Biochem. Biophys. Res. Commun.
Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles
Vit. Horm.
Gas exchange in chronic thromboembolism after pulmonary thromboendarterectomy
Chest
Importin β recognizes parathyroid hormone-related protein with high affinity and mediates its nuclear import in the absence of importin α
J. Biol. Chem.
Parathyroid hormone-related peptide and 8701-BC breast cancer cell growth and invasion in vitro: evidence for growth-inhibiting and invasion-promoting effects
Mol. Cell. Endocrinol.
Activity-dependent expression of parathyroid hormone-related protein (PTHrP) in rat cerebellar granule neurons. Requirement of PTHrP for the activity-dependent survival of granule neurons
J. Biol. Chem.
Parathyroid hormone (PTH) and PTH-related protein stimulate surfactant phospholipid synthesis in rat fetal lung, apparently by a mesenchymal–epithelial mechanism
Biochim. Biophys. Acta
Parathyroid hormone-related protein upregulates integrin expression via an intracrine pathway in PC-3 prostate cancer cells
Regul. Pept.
PTH-related protein enhances MCF-7 breast cancer cell adhesion, migration, and invasion via an intracrine pathway
Exp. Cell. Res.
Parathyroid hormone-related protein in epithelial lining fluid in humans negatively correlates with the severity of lung injury
Chest
The nucleolar targeting signal (NTS) of parathyroid hormone-related protein mediates endocytosis and nucleolar translocation
J. Bone Miner. Res.
Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium
Proc. Natl. Acad. Sci. U.S.A.
The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen
Lab. Invest.
Parathyroid hormone-related peptide is a potent tumor angiogenic factor
Endocrinology
Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues
J. Clin. Endocrinol. Metab.
Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia
Am. Rev. Respir. Dis.
Parathyroid hormone-related peptide is a naturally occurring, protein kinase A-dependent angiogenesis inhibitor
Nat. Med.
The human PTH2 receptor: binding and signal transduction properties of the stably expressed recombinant receptor
Endocrinology
Regulation of branching morphogenesis in the lung by parathyroid hormone-related protein
Bone
Parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor expression and mitogenic responses in human breast cancer cell lines
Br. J. Cancer.
Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases
Cancer Res.
All major lung cancer cell types produce parathyroid hormone-like protein: heterogeneity assessed by high performance liquid chromatography
Endocrinology
Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide
N. Engl. J. Med.
Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer
N. Engl. J. Med.
Immunocytochemical localization of parathyroid hormone-like peptide in the rat fetus
Cancer Res.
Parathyroid hormone-related protein (PTHrP) mRNA splicing and parathyroid hormone/PTHrP receptor mRNA expression in human placenta and fetal membranes
J. Mol. Endocrinol.
Lung tumours immunoreactive for parathyroid hormone-related peptide: analysis of serum calcium levels and tumour type
J. Pathol.
Parathyroid hormone-like protein is a secretory product of atrial myocytes
J. Clin. Invest.
Immunoassays for PTH and PTHrP
Comparative tissue distribution of the processing enzymes “prohormone thiol protease,” and prohormone convertases 1 and 2, in human PTHrP-producing cell lines and mammalian neuroendocrine tissues
Endocrine
Parathyroid hormone-related protein as a growth regulator of prostate carcinoma
Cancer Res.
Enhanced growth of MCF-7 breast cancer cells overexpressing parathyroid hormone-related peptide
Endocrinology
Minireview: parathyroid hormone-related protein as an intracrine factor-trafficking mechanisms and functional consequences
Endocrinology
The tetrabasic KKKK 147–150 motif determines intracrine regulatory effects of PTHrP 1–173 on chondrocyte PPi metabolism and matrix synthesis
Endocrinology
Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis
J. Clin. Invest.
Alveolar epithelial cells express and secrete parathyroid hormone-related protein
Am. J. Respir. Cell Mol. Biol.
Parathyroid hormone-related protein, an autocrine regulatory factor for alveolar epithelial cells
Am. J. Physiol.
Parathyroid hormone-related protein, an autocrine growth inhibitor of alveolar type II cells
Am. J. Physiol.
Cited by (25)
Widespread disturbance in extracellular matrix collagen biomarker responses to teriparatide therapy in osteogenesis imperfecta
2021, BoneCitation Excerpt :It plays a critical role in muscle satellite cell self-renewal [53], pathogenic variants in genes encoding the alpha chains of type VI collagen result in Bethlem and Ullrich congenital muscular dystrophy [54], and C6M has been shown to be related to lean mass [39,55] [56]. In lung, biomarkers for type VI are elevated in pulmonary fibrosis, and PTH/PTHrP receptors are present in lung [57]. Type VI collagen is also a component bone, albeit a minor one, and of articular cartilage [58].
Effect of high fat diet on pulmonary expression of parathyroid hormone-related protein and its downstream targets
2016, HeliyonCitation Excerpt :Several mechanisms are known by which PTHrP stabilizes lung function. These are its vasodilating effect that improves perfusion, its effect on surfactant formation that improves oxygen uptake, and its inhibitory effect on transdifferentiation of lipofibroblasts into myofibroblasts [8, 23]. We proved the latter assumption under conditions of HFD-dependent activation of the PTHrP system by studying the pulmonary expression of elastin.
E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors
2016, Proceedings of the National Academy of Sciences of the United States of America