The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Andrew F Stewart - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid hormone related Protein as a regulator of prb and the cell cycle in arterial smooth muscle
Circulation, 2004Co-Authors: Nathalie Fiaschitaesch, Karen K Takane, Sophia Masters, Juan Carlos Lopeztalavera, Andrew F StewartAbstract:Background— Parathyroid hormone–related Protein (PTHrP), a normal product of arterial vascular smooth muscle (VSM), contains a nuclear localization signal (NLS) and at least 2 translational initiation sites, one that generates a conventional signal peptide and one that disrupts the signal peptide. These unusual features allow PTHrP either to be secreted in a paracrine/autocrine fashion, and thereby to inhibit arterial smooth muscle proliferation, or to be retained within the cytosol and to translocate into the nucleus, thereby serving as an intracrine stimulator of smooth muscle proliferation. Methods and Results— Here, we demonstrate 2 important findings. First, PTHrP dramatically increases the percentage of VSM cells in the S and in G2/M phases of the cell cycle. These effects require critical serine and threonine residues at positions Ser119, Ser130, Thr132, and Ser138 in the carboxy-terminus of PTHrP and are associated with the phosphorylation of the key cell cycle checkpoint regulator retinoblastoma ...
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overexpression of Parathyroid hormone related Protein inhibits pancreatic β cell death in vivo and in vitro
Diabetes, 2002Co-Authors: Ana Cebrian, Andrew F Stewart, Karen K Takane, Adolfo Garciaocana, Darinka Sipula, Rupangi C VasavadaAbstract:Pancreatic β-cell survival is critical in the setting of diabetes as well as in islet transplantation. Transgenic mice overexpressing Parathyroid Hormone-Related Protein (PTHrP) targeted to β-cells using the rat insulin II promoter (RIP) display hyperinsulinemia, hypoglycemia, and islet hyperplasia, without a concomitant increase in β-cell proliferation rate or enlargement of individual β-cell size. Thus, the mechanism for increased β-cell mass is unknown. In this study, we demonstrated that β-cells of transgenic mice are resistant to the cytotoxic effects of streptozotocin (STZ) in vivo, as documented by a sixfold reduction in the rate of STZ-induced β-cell death in RIP-PTHrP mice relative to their normal siblings. The reduced cell death in transgenic mice is due neither to their increased islet mass nor to a decrease in their sensing of STZ, but rather results from PTHrP-induced resistance to β-cell death. This is also demonstrated in vitro by markedly reduced cell death rates observed in β-cells of transgenic mice compared with normal mice when cultured in the absence of serum and glucose or in the presence of STZ. Finally, we demonstrated that NH 2 -terminal PTHrP inhibits β-cell death. These findings support the concept that PTHrP overexpression increases islet mass in transgenic mice through inhibition of β-cell death.
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midregion Parathyroid hormone related Protein inhibits growth and invasion in vitro and tumorigenesis in vivo of human breast cancer cells
Journal of Bone and Mineral Research, 2001Co-Authors: Claudio Luparello, Rita Romanotto, Annalisa Tipa, Rosalia Sirchia, Nieves Olmo, Isabel Lopez De Silanes, Javier Turnay, Antonia M Lizarbe, Andrew F StewartAbstract:Parathyroid Hormone-Related Protein (PTHrP) is critical for normal mammary development and is overexpressed by breast cancers. PTHrP is a peptide hormone that undergoes extensive post-translational processing, and PTHrP(38–94)-amide is one of the mature secretory forms of the peptide. In this study, we explored the effect of PTHrP(38–94)-amide in a panel of six breast cancer cell lines “in vitro” and in MDA-MB231 cells “in vivo” specifically examining cell viability, proliferation, invasiveness, and growth in nude mice. PTHrP(38–94)-amide markedly inhibited proliferation and also caused striking toxicity and accelerated cell death in breast cancer cells. In addition, direct injection of PTHrP(38–94)-amide into MDA-MB231 breast cancer cells passaged in immunodeficient mice produced a marked reduction in tumor growth. These studies (i) indicate breast cancer cells are one of the few tissues in which specific effects of midregion PTHrP have been established to date, (ii) support a role for midregion secretory forms of PTHrP in modulating not only normal but also pathological mammary growth and differentiation, (iii) add further evidence for the existence of a specific midregion PTHrP receptor, and (iv) provide a novel molecule for modeling of small molecule analogues that may have anti-breast cancer effects.
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overexpression of Parathyroid hormone related Protein in the pancreatic islets of transgenic mice causes islet hyperplasia hyperinsulinemia and hypoglycemia
Journal of Biological Chemistry, 1996Co-Authors: Rupangi C Vasavada, William M Philbrick, W J Burtis, Pamela Dann, Christi Cavaliere, Joseph A Dercole, Alex L Madlener, Kathleen C Zawalich, Walter S Zawalich, Andrew F StewartAbstract:Parathyroid Hormone-Related Protein (PTHrP) is produced by the pancreatic islet. It also has receptors on islet cells, suggesting that it may serve a paracrine or autocrine role within the islet. We have developed transgenic mice, which overexpress PTHrP in the islet through the use of the rat insulin II promoter (RIP). Glucose homeostasis in these mice is markedly abnormal; RIP-PTHrP mice are hypoglycemic in the post-prandial and fasting states and display inappropriate hyperinsulinemia. At the end of a 24-hour fast, blood glucose values are 49 mg/dl in RIP-PTHrP mice, as compared to 77 mg/dl in normal littermates; insulin concentrations at this time are 6.3 and 3.9 ng/ml, respectively. Islet perifusion studies failed to demonstrate abnormalities in insulin secretion. In contrast, quantitative islet histomorphometry demonstrates that the total islet number and total islet mass are 2-fold higher in RIP-PTHrP mice than in their normal littermates. PTHrP very likely plays a normal physiologic role within the pancreatic islet. This role is most likely paracrine or autocrine. PTHrP appears to regulate insulin secretion either directly or indirectly, through developmental or growth effects on islet mass. PTHrP may have a role as an agent that enhances islet mass and/or enhances insulin secretion.
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Parathyroid hormone related Protein as a prohormone posttranslational processing and receptor interactions
Endocrine Reviews, 1994Co-Authors: John J Orloff, Daphne Reddy, Anne E De Papp, Kai H Yang, Neil E Soifer, Andrew F StewartAbstract:Parathyroid Hormone-Related Protein (PTHrP) bioactivity was identified in 1983 in tumors associated with humoral hypercalcemia of malignancy (HHM). The N-terminal amino acid and complementary DNA (cDNA) sequences were identified in 1987. The search for the causative agent of HHM was fueled by the frequency with which HHM occurs, by the severe complications of hypercalcemia (coma, renal failure, death), and by the identification in clinical and laboratory studies of a novel calcium-regulating hormone that could be postulated as the cause of HHM. It was expected at the time that this search would lead to the purification of the responsible “humor,” and that that “humor,” when identified, would prove to have some normal physiological role. It was not anticipated that the “humor” would prove to be produced by almost every type of cell in the body at some stage of development, or that the search for the novel “humor” would lead to the identification of an unusually large, complicated, and interesting family of...
Thomas J. Rosol - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid hormone related Protein promotes bone loss in t cell leukemia as well as in solid tumors
Leukemia & Lymphoma, 2020Co-Authors: Nicole A Kohart, Said M Elshafae, Aylin A Demirer, Wessel P Dirksen, Justin Breitbach, Sherry T Shu, Jingyu Xiang, Katherine N Weilbaecher, Thomas J. RosolAbstract:Parathyroid Hormone-Related Protein (PTHrP) and macrophage inflammatory Protein-1α (MIP-1α) are important factors that increase bone resorption and hypercalcemia in adult T-cell leukemia (ATL). We ...
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Vet. Pathol. 27:89-95 (1990) Identification of Parathyroid Hormone-Related Protein in Canine Apocrine Adenocarcinoma of the Anal Sac
2016Co-Authors: Thomas J. Rosol, Peter R Ebeling, Charles C. Capen, Larry J Suva, C L Steinmeyer, J Hayman, J. A. Danks, T J MartinAbstract:Abstract. The presence of Parathyroid Hormone-Related Protein (PTHrP) in the apocrine adenocarcinoma tumor line (CAC-8) derived from a hypercalcemic dog was demonstrated by western and northern blot analyses. Western blots of CAC-8 tumor extracts revealed a major Protein with a molecular weight of approximately 18,000 daltons that cross-reacted with antiserum to human PTHrP. Northern blots demonstrated multiple-sized messenger RNA transcripts in CAC-8 that hybridized to a full-length cDNA probe to human PTHrP. Adenocarcinomas derived from apocrine glands of the anal sac also were stained immunohistochemically for antigens that cross-react with antiserum to human PTHrP. The tumor line (CAC-8) maintained in nude mice stained positively for PTHrP in 13 of 24 tumors. Three of ten apocrine adenocarcinomas from dogs with hypercalcemia stained for PTHrP, whereas zero of ten tumors were positive from normocalcemic dogs. Normal canine epidermal keratinocytes and areas of squamous metaplasia in a perianal gland carcinoma also were positive for PTHrP. These data demonstrated that canine tissues contained a homologue to human PTHrP that likely is important in the pathogenesis of humoral hypercalcemia of malignancy. Key words: Anal sac; apocrine adenocarcinoma; dog; humoral hypercalcemia of malignancy; hypercalcemia; Parathyroid Hormone-Related Protein. The adenocarcinoma derived from apocrine gland
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bone invasive oral squamous cell carcinoma in cats pathology and expression of Parathyroid hormone related Protein
Veterinary Pathology, 2011Co-Authors: Chelsea K Martin, Sarah H Tannehillgregg, Tobie D Wolfe, Thomas J. RosolAbstract:Feline oral squamous cell carcinoma (OSCC) is the most common oral tumor in cats. There is no effective treatment, and the average duration of survival after diagnosis is only 2 months. Feline OSCC is frequently associated with osteolysis; however, the mechanisms responsible are unknown. The objective of this study was to characterize the epidemiology and pathology of bone-invasive OSCC in cats and to determine the expression of select bone resorption agonists. In sum, 451 cases of feline OSCC were evaluated. There was no sex or breed predisposition, although there were more intact cats in the OSCC group compared to the control group. Gingiva was the most common site, followed by the sublingual region and tongue. Cats with lingual OSCC were younger (mean, 11.9 years) compared to cats with gingival OSCC (mean, 13.6 years). In addition to osteolysis, there was periosteal new bone formation, osseous metaplasia of tumor stroma, and direct apposition of OSCC to fragments of bone, suggestive of bone-binding behavior. Eighty-two cases were selected for immunohistochemical detection of Parathyroid Hormone-Related Protein (PTHrP). Specimens with osteolysis had increased PTHrP expression and nuclear localization, compared to OSCC without osteolysis. Thirty-eight biopsies of OSCC with osteolysis were evaluated for tumor necrosis factor α expression, and only 4 biopsies had such expression in a small proportion of tumor cells. Increased tumor expression of PTHrP and increased localization of PTHrP to the nucleus were associated with osteolysis and may play an important role in bone resorption and tumor invasion in cats with OSCC.
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Parathyroid hormone related Protein and ezrin are up regulated in human lung cancer bone metastases
Clinical & Experimental Metastasis, 2007Co-Authors: Sarah H Tannehillgregg, Xiyun Deng, Murali V P Nadella, Andrea L Levine, Ya Cao, Thomas J. RosolAbstract:Lung cancer often metastasizes to bone in patients with advanced disease. Identification of the factors involved in the interactions between lung cancer cells and bone will improve the prevention and treatment of bone metastases. We identified changes in metastasis-related gene expression of human HARA lung squamous carcinoma cells co-cultured with neonatal mouse calvariae using a pathway-specific microarray analysis. Nine genes were up-regulated and two genes down-regulated in HARA cells co-cultured with mouse calvariae. Five of the nine up-regulated genes, including caveolin 1, CD44, EphB2, ezrin, and Parathyroid Hormone-Related Protein (PTHrP), and one down-regulated gene, SLPI, were further confirmed by Reverse transcription-polymerase chain reaction (RT-PCR). A mouse model was subsequently used to study the role of PTHrP and ezrin in bone metastasis in vivo. PTHrP (all three isoforms) and ezrin were up-regulated in HARA cells at sites of bone metastasis as detected by RT-PCR and immunohistochemistry. The PTHrP 141 mRNA isoform was increased by the greatest extent (13.9-fold) in bone metastases compared to PTHrP 139 and PTHrP 173 mRNA. We then generated a HARA cell line in which PTHrP expression was inducibly silenced by RNA interference. Silencing of PTHrP expression caused significant reduction of submembranous F-actin and decreased HARA cell invasion. Ezrin up-regulation was confirmed by Western blots on HARA cells co-cultured with adult mouse long bones. Further, Transforming growth factor beta (TGF-β) was identified as one of the factors in the bone microenvironment that was responsible for the up-regulation of ezrin. The identification of PTHrP and ezrin as important regulators of lung cancer bone metastasis offers new mechanistic insights into the metastasis of lung cancer and provides potential targets for the prevention and treatment of lung cancer metastasis.
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Parathyroid hormone related Protein as a growth regulator of prostate carcinoma
Cancer Research, 1999Co-Authors: Kristiann M Dougherty, Eric A G Blomme, Janet E Henderson, Thomas J. Rosol, Kenneth J. Pienta, Laurie K MccauleyAbstract:Parathyroid Hormone-Related Protein (PTHrP) is produced by prostate carcinoma cells and tumors, but little is known of its role in prostate carcinogenesis. The goal of this study was to evaluate PTHrP expression in the regulation of prostate carcinoma growth using human and animal models. PTHrP expression was assessed in prostate cancer cell lines in vitro. Seven of nine cell lines produced PTHrP, and increased expression was seen during cell proliferation. The MatLyLu rat prostate carcinoma model was used to determine the effects of PTHrP overexpression on prostate tumor growth. PTHrP overexpression did not alter proliferation of the cells in vitro. However, when PTHrP-overexpressing cells were injected into rat hind limbs, primary tumor growth and tumor size were significantly enhanced as compared with control cells. To evaluate PTHrP in human prostate carcinoma patients, immunohistochemistry was performed on metastatic bone lesions. Immunolocalization of PTHrP Protein was found in the cytoplasm and nucleus of cancer cells in the bone microenvironment. Because nuclear localization of PTHrP has been associated with an inhibition of apoptosis, the ability of full-length PTHrP to protect prostate cancer cells from apoptotic stimuli was examined. Cells transfected with full-length PTHrP showed significantly increased cell survival after exposure to apoptotic agents as compared with cells producing no PTHrP (plasmid control) or cells transfected with PTHrP lacking its nuclear localization signal. To determine the mechanism of action of PTHrP in prostate cancer cells, the Parathyroid hormone/PTHrP receptor status of the cells was determined. These cell lines did not demonstrate Parathyroid hormone/PTHrP receptor-mediated binding of iodinated PTHrP or steady-state receptor message by Northern blot analysis, but they did have a detectable receptor message by reverse transcription-PCR analysis. In summary, PTHrP is expressed in many prostate cancer cell lines in vitro and in metastatic bone lesions in vivo. PTHrP expression positively influences primary tumor size in vivo and protects cells from apoptotic stimuli. These data suggest that PTHrP plays an important role in the promotion of prostate tumor establishment and/or progression.
Leonard J Deftos - One of the best experts on this subject based on the ideXlab platform.
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Parathyroid hormone related Protein promotes epithelial to mesenchymal transition in prostate cancer
PLOS ONE, 2014Co-Authors: Weg M Ongkeko, Doug W Burton, Alan Kiang, Eric L Abhold, Selena Z Kuo, Elham Rahimy, Meng Yang, Robert M Hoffman, Jessica Wangrodriguez, Leonard J DeftosAbstract:Parathyroid Hormone-Related Protein (PTHrP) possesses a variety of physiological and developmental functions and is also known to facilitate the progression of many common cancers, notably their skeletal invasion, primarily by increasing bone resorption. The purpose of this study was to determine whether PTHrP could promote epithelial-to-mesenchymal transition (EMT), a process implicated in cancer stem cells that is critically involved in cancer invasion and metastasis. EMT was observed in DU 145 prostate cancer cells stably overexpressing either the 1-141 or 1-173 isoform of PTHrP, where there was upregulation of Snail and vimentin and downregulation of E-cadherin relative to parental DU 145. By contrast, the opposite effect was observed in PC-3 prostate cancer cells where high levels of PTHrP were knocked-down via lentiviral siRNA transduction. Increased tumor progression was observed in PTHrP-overexpressing DU 145 cells while decreased progression was observed in PTHrP-knockdown PC-3 cells. PTHrP-overexpressing DU 145 formed larger tumors when implanted orthoptopically into nude mice and in one case resulted in spinal metastasis, an effect not observed among mice injected with parental DU 145 cells. PTHrP-overexpressing DU 145 cells also caused significant bone destruction when injected into the tibiae of nude mice, while parental DU 145 cells caused little to no destruction of bone. Together, these results suggest that PTHrP may work through EMT to promote an aggressive and metastatic phenotype in prostate cancer, a pathway of importance in cancer stem cells. Thus, continued efforts to elucidate the pathways involved in PTHrP-induced EMT as well as to develop ways to specifically target PTHrP signaling may lead to more effective therapies for prostate cancer.
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prognostic implications of Parathyroid hormone related Protein in males and females with non small cell lung cancer
Clinical Lung Cancer, 2011Co-Authors: Philippe R Montgrain, Leonard J Deftos, Douglas A Arenberg, Ann Tipps, Rick Quintana, Shannon Carskadon, Randolph H HastingsAbstract:Abstract Background Non–small-cell lung carcinoma immunoreactivity for Parathyroid Hormone-Related Protein has been associated with increased survival in female patients but not in male patients. The current investigation attempted to substantiate this finding in 2 new patient groups. Methods Patients were divided into groups with and without immunoreactivity for a carboxyl-terminal Parathyroid Hormone-Related Protein epitope assessed in deparaffinized sections by a blinded observer. One group included 85 female patients with stage I lung cancer, and the second group had 48 female and 66 male patients with stage I-IV lung cancer. Survival times were compared by the log-rank test between groups separated by tumor Parathyroid Hormone-Related Protein status. Results Parathyroid Hormone-Related Protein was present in 70%-80% of the patients, independent of sex, stage, and smoking history. In the females with stage I lung cancer, Parathyroid Hormone-Related Protein increased median survival from 25 to 60 months ( P P Conclusion This study verifies that Parathyroid Hormone-Related Protein is a sex-dependent survival factor for non–small-cell lung carcinoma, that it correlates with disease-free survival, and that the association with survival holds for women with early-stage disease as well as more advanced cancer. Thus, the Protein could find use as a prognostic indicator and could be a target for therapy.
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Parathyroid hormone related Protein varies with sex and androgen status in nonsmall cell lung cancer
Cancer, 2007Co-Authors: Philippe R Montgrain, Leonard J Deftos, Rick Quintana, Yvette Rascon, Douglas Burton, Andrea L Casillas, Randolph H HastingsAbstract:BACKGROUND. In nonsmall cell lung cancer, tumor Parathyroid Hormone-Related Protein (PTHrP) expression predicts longer survival in women but not in men. To explain the sex-dependent survival effect, the authors proposed that hormonal influences decrease PTHrP in men versus women, that PTHrP inhibits tumor growth, and that the effect is greater in women than in men. The objectives of this study were to compare lung carcinoma PTHrP expression and carcinoma growth in male and female mice and to determine whether gonadal steroids regulate PTHrP in lung cancer cells. METHODS. Tumor PTHrP content was measured by immunoassay, and tumor burden was assessed with multiple measures in BEN squamous cell orthotopic lung carcinomas in athymic mice. In addition, lung adenocarcinoma PTHrP messenger RNA (mRNA) values determined by microarray analyses were compared between men and women. Cultured lung cancer cells were assayed for PTHrP after treatment with estradiol or R1881, a synthetic androgen. RESULTS. Lung carcinomas contained approximately 3 times more PTHrP in female mice than in male mice. Similarly, levels of PTHrP mRNA were significantly greater in adenocarcinomas from patients who were women than from patients who were men. Male mice had greater tumor burden than female mice. Androgen treatment reduced PTHrP in 3 lung cancer lines. Estradiol had no effect. Testosterone treatment also reduced lung carcinoma PTHrP in female mice. CONCLUSIONS. Lung carcinomas in females expressed more PTHrP than in males possibly because of negative regulation by androgens in males. Female mice with higher tumor PTHrP content had significantly less tumor burden than male mice, supporting the hypothesis that PTHrP inhibits tumor growth. Cancer 2007. © 2007 American Cancer Society.
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Parathyroid hormone related Protein as a novel tumor marker in pancreatic adenocarcinoma
Pancreas, 2002Co-Authors: Michael Bouvet, Meng Yang, Robert M Hoffman, Stephanie R Nardin, Douglas W Burton, Xiaoen Wang, Eugene Baranov, Cynthia Behling, A R Moossa, Leonard J DeftosAbstract:Introduction: Parathyroid Hormone-Related Protein (PTHrP) can act as an oncoProtein to regulate the growth and proliferation of many common malignancies, including pancreatic cancer. Previous studies have shown that PTHrP is produced by human pancreatic cancer cell lines, can be shown in the cytoplasm and nucleus of paraffin-embedded pancreatic adenocarcinoma tumor specimens, and is secreted into the media of cultured pancreatic adenocarcinoma cells. We hypothesized that PTHrP could serve as a tumor-marker for growth of pancreatic cancer in vivo. Aim and Methodology: To test this hypothesis, we used an orthotopic model developed in our laboratory of the PTHrP-producing human pancreatic cancer line, BxPC-3. This tumor was stably transduced with green fluorescence Protein (GFP) to facilitate visualization of tumor growth and metastases. At early (5 weeks) and late (13 weeks) time points after surgical orthotopic implantation, serum PTHrP was measured and primary and metastatic tumor burden was determined for each mouse by assessing GFP expression. Results: By 5 weeks after surgical orthotopic implantation (early group), the mean serum PTHrP level was 33.3 pg/mL. In contrast, by 13 weeks after surgical orthotopic implantation (late group), the mean serum PTHrP level increased to 158.5 pg/mL. These differences were highly significant (p < 0.001, Student t test). Numerous metastatic lesions were readily visualized by GFP in the late group. Serum PTHrP levels measured by immunoassay correlated with primary pancreatic tumor weights and serum calcium levels (p <0.01). PTHrP levels were not detectable (<21 pg/mL) in any of the 10 control mice with no tumor. Western blotting of BxPC-3-GFP tumor lysates confirmed the presence of PTHrP. BxPC-3-GFP tumor tissue stained with antibody to PTHrP. Conclusion: These results indicate that PTHrP can serve as a tumor marker in animal models of pancreatic cancer and may be a useful tumor marker for clinical pancreatic adenocarcinoma.
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granin a Parathyroid hormone related Protein and calcitonin gene products in neuroendocrine prostate cancer
The Prostate, 1998Co-Authors: Leonard J DeftosAbstract:BACKGROUND The importance of the expression of granin A (GRN-A, chromogranin-A), calcitonin (CT) gene products (CGPs), and Parathyroid Hormone-Related Protein (PTHrP) has become appreciated in the neuroendocrine (NE) differentiation of prostate cancer. We have studied the prostate expression of these three NE cell products with in vivo and in vitro methods. METHODS GRN-A secretion was measured by immunoassay in serum samples from patients with prostate cancer. Immunohistology procedures were used to assess GRN-A, CGPs, and PTHrP expression in paraffin-embedded prostate tissue samples. Serum and tumor findings were evaluated according to the patient's clinical status. All three substances were also studied in prostate cancer cell cultures. RESULTS GRN-A, PTHrP, and CGPs were all secreted products of prostate cancer. Our studies demonstrated that GRN-A can serve as a prostate cancer serum and tumor marker with clinical value for both diagnosis and prognosis. Elevated serum GRN-A levels identified patients with prostate cancer, including some who did not have elevated serum prostate-specific antigen (PSA) levels. Serum GRN-A concentrations also had prognostic value for prostate cancer. PTHrP and CGPs were expressed in prostate cancer in addition to GRN-A, and all three were secreted by prostate cells in culture. Each had effects on prostate cell growth. CONCLUSIONS GRN-A, PTHrP, and CGPs are produced and secreted by prostate cells. These three NE cell products can serve as tumor and markers for prostate cancer that have diagnostic and prognostic value. In addition, their derived peptides regulate prostate cell growth. However, studies more conclusive than the preliminary observations of our group and of other investigators are needed to define the roles of PTHrP, GRN-A, and CGPs in prostate cancer. Prostate Supplement 8:23–31, 1998. © 1998 Wiley-Liss, Inc.
Nathalie Fiaschitaesch - One of the best experts on this subject based on the ideXlab platform.
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calcium sensing receptor promotes breast cancer by stimulating intracrine actions of Parathyroid hormone related Protein
Cancer Research, 2016Co-Authors: Wonnam Kim, Nathalie Fiaschitaesch, Joshua Vanhouten, Pamela Dann, Farzin Takyar, Karena L Swan, Jaekwang Jeong, Catherine A W Sullivan, Wenhan Chang, John J WysolmerskiAbstract:Parathyroid Hormone-Related Protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, but it is not known how PTHrP is upregulated during breast tumorigenesis. Here we report a central role in this process for CaSR, a calcium-sensing receptor which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo. Tissue-specific disruption of the CaSR gene in mammary epithelial cells in MMTV-PymT mice inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. These antiproliferative effects appeared to be mediated by nuclear actions of PTHrP that decreased p27kip1 levels and prevented nuclear accumulation of the pro-apoptotic factor AIF. Taken together, our findings suggest CaSR-PTHrP interactions as a locus for the development of therapeutic agents to limit metastasis to bone and other microenvironments where elevated PTHrP and extracellular calcium have been causally implicated.
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c myc and skp2 coordinate p27 degradation vascular smooth muscle proliferation and neointima formation induced by the Parathyroid hormone related Protein
Endocrinology, 2012Co-Authors: Brian M Sicari, Karen K Takane, Ronnie Troxell, Fatimah G Salim, Mansoor Tanwir, Nathalie FiaschitaeschAbstract:Parathyroid Hormone-Related Protein (PTHrP) contains a classical bipartite nuclear localization signal. Nuclear PTHrP induces proliferation of arterial vascular smooth muscle cells (VSMC). In the arterial wall, PTHrP is markedly up-regulated in response to angioplasty and promotes arterial restenosis. PTHrP overexpression exacerbates arterial restenosis, and knockout of the PTHrP gene results in decreased VSMC proliferation in vivo. In arterial VSMC, expression of the cell cycle inhibitor, p27, rapidly decreases after angioplasty, and replacement of p27 markedly reduces neointima development. We have shown that PTHrP overexpression in VSMC leads to p27 down-regulation, mostly through increased proteosomal degradation. Here, we determined the molecular mechanisms through which PTHrP targets p27 for degradation. S-phase kinase-associated Protein 2 (skp2) and c-myc, two critical regulators of p27 expression and stability, and neointima formation were up-regulated in PTHrP overexpression in VSMC. Normalizatio...
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Parathyroid hormone related Protein as a regulator of prb and the cell cycle in arterial smooth muscle
Circulation, 2004Co-Authors: Nathalie Fiaschitaesch, Karen K Takane, Sophia Masters, Juan Carlos Lopeztalavera, Andrew F StewartAbstract:Background— Parathyroid hormone–related Protein (PTHrP), a normal product of arterial vascular smooth muscle (VSM), contains a nuclear localization signal (NLS) and at least 2 translational initiation sites, one that generates a conventional signal peptide and one that disrupts the signal peptide. These unusual features allow PTHrP either to be secreted in a paracrine/autocrine fashion, and thereby to inhibit arterial smooth muscle proliferation, or to be retained within the cytosol and to translocate into the nucleus, thereby serving as an intracrine stimulator of smooth muscle proliferation. Methods and Results— Here, we demonstrate 2 important findings. First, PTHrP dramatically increases the percentage of VSM cells in the S and in G2/M phases of the cell cycle. These effects require critical serine and threonine residues at positions Ser119, Ser130, Thr132, and Ser138 in the carboxy-terminus of PTHrP and are associated with the phosphorylation of the key cell cycle checkpoint regulator retinoblastoma ...
John J Wysolmerski - One of the best experts on this subject based on the ideXlab platform.
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calcium sensing receptor promotes breast cancer by stimulating intracrine actions of Parathyroid hormone related Protein
Cancer Research, 2016Co-Authors: Wonnam Kim, Nathalie Fiaschitaesch, Joshua Vanhouten, Pamela Dann, Farzin Takyar, Karena L Swan, Jaekwang Jeong, Catherine A W Sullivan, Wenhan Chang, John J WysolmerskiAbstract:Parathyroid Hormone-Related Protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, but it is not known how PTHrP is upregulated during breast tumorigenesis. Here we report a central role in this process for CaSR, a calcium-sensing receptor which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo. Tissue-specific disruption of the CaSR gene in mammary epithelial cells in MMTV-PymT mice inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. These antiproliferative effects appeared to be mediated by nuclear actions of PTHrP that decreased p27kip1 levels and prevented nuclear accumulation of the pro-apoptotic factor AIF. Taken together, our findings suggest CaSR-PTHrP interactions as a locus for the development of therapeutic agents to limit metastasis to bone and other microenvironments where elevated PTHrP and extracellular calcium have been causally implicated.
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the calcium sensing receptor regulates mammary gland Parathyroid hormone related Protein production and calcium transport
Journal of Clinical Investigation, 2004Co-Authors: Joshua Vanhouten, Pamela Dann, Grace Mcgeoch, Edward M Brown, Karen J Krapcho, Margaret C Neville, John J WysolmerskiAbstract:The transfer of calcium from mother to milk during lactation is poorly understood. In this report, we demonstrate that Parathyroid hormone–related Protein (PTHrP) production and calcium transport in mammary epithelial cells are regulated by extracellular calcium acting through the calcium-sensing receptor (CaR). The CaR becomes expressed on mammary epithelial cells at the transition from pregnancy to lactation. Increasing concentrations of calcium, neomycin, and a calcimimetic compound suppress PTHrP secretion by mammary epithelial cells in vitro, whereas in vivo, systemic hypocalcemia increases PTHrP production, an effect that can be prevented by treatment with a calcimimetic. Hypocalcemia also reduces overall milk production and calcium content, while increasing milk osmolality and Protein concentrations. The changes in milk calcium content, milk osmolality, and milk Protein concentration were mitigated by calcimimetic infusions. Finally, in a three-dimensional culture system that recapitulates the lactating alveolus, activation of the basolateral CaR increases transcellular calcium transport independent of its effect on PTHrP. We conclude that the lactating mammary gland can sense calcium and adjusts its secretion of calcium, PTHrP, and perhaps water in response to changes in extracellular calcium concentration. We believe this defines a homeostatic system that helps to match milk production to the availability of calcium.
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temporally regulated overexpression of Parathyroid hormone related Protein in the mammary gland reveals distinct fetal and pubertal phenotypes
Journal of Endocrinology, 2001Co-Authors: Maureen E Dunbar, Pamela Dann, C W Brown, J Van Houton, Barbara E Dreyer, W P Philbrick, John J WysolmerskiAbstract:We have previously demonstrated that overexpression of Parathyroid Hormone-Related Protein (PTHrP) in the mammary glands of transgenic mice results in defects in ductal elongation and branching during puberty and in lobuloalveolar development during pregnancy. In addition, we have shown that PTHrP is necessary for the formation of the initial ductal tree during embryonic mammary development. In order to examine the effect of varying the timing of PTHrP overexpression on mammary development, we created tetracycline-regulated, K14tTA/TetO-PTHrP double transgenic mice. In this report, we document that this ‘tet-off’ system directs transgene expression to the mammary gland and that it is fully repressed in the presence of tetracycline. Using these mice, we demonstrate that transient overexpression of PTHrP before birth causes defects in ductal branching during puberty and that overexpression of PTHrP during puberty decreases the rate of ductal elongation. Furthermore, we demonstrate that if PTHrP overexpression is initiated after ductal morphogenesis is completed, lobuloalveolar development is unaffected. Finally, we demonstrate that the impairment in ductal elongation caused by PTHrP is associated with an increase in the basal rate of epithelial cell apoptosis in terminal end buds and a failure to increase end bud cell proliferation and decrease apoptosis in response to estrogen and progesterone.
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Parathyroid hormone related Protein a developmental regulatory molecule necessary for mammary gland development
Journal of Mammary Gland Biology and Neoplasia, 1999Co-Authors: Maureen E Dunbar, John J WysolmerskiAbstract:Parathyroid Hormone-Related Protein (PTHrP) wasoriginally identified as the tumor factor responsiblefor a clinical syndrome known as humoral hypercalcemiaof malignancy. It is now appreciated that PTHrP3 is a developmental regulatory moleculeexpressed during the formation of a wide variety oforgans. Recently, our laboratory has demonstrated thatPTHrP is necessary for mammary gland development. Ourstudies have suggested that this molecule participatesin the regulation of epithelial-mesenchymal interactionsduring embryonic mammary development and perhaps alsoduring adolescent ductal morphogenesis. In addition, it has been suggested that PTHrP plays acritical role in the establishment of bone metastases inbreast cancer. In this article, we will discuss thecurrent knowledge of the mechanisms underlying PTHrPs actions during normal mammary development andin breast cancer.
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rescue of the Parathyroid hormone related Protein knockout mouse demonstrates that Parathyroid hormone related Protein is essential for mammary gland development
Development, 1998Co-Authors: John J Wysolmerski, William M Philbrick, Maureen E Dunbar, Beate Lanske, Henry M Kronenberg, Arthur E BroadusAbstract:Parathyroid Hormone-Related Protein (PTHrP) was originally discovered as a tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in normal tissues and growing evidence suggests that it is an important developmental regulatory molecule. We had previously reported that overexpression of PTHrP in the mammary glands of transgenic mice impaired branching morphogenesis during sexual maturity and early pregnancy. We now demonstrate that PTHrP plays a critical role in the epithelial-mesenchymal communications that guide the initial round of branching morphogenesis that occurs during the embryonic development of the mammary gland. We have rescued the PTHrP-knockout mice from neonatal death by transgenic expression of PTHrP targeted to chondrocytes. These rescued mice are devoid of mammary epithelial ducts. We show that disruption of the PTHrP gene leads to a failure of the initial round of branching growth that is responsible for transforming the mammary bud into the rudimentary mammary duct system. In the absence of PTHrP, the mammary epithelial cells degenerate and disappear. The ability of PTHrP to support embryonic mammary development is a function of amino-terminal PTHrP, acting via the PTH/PTHrP receptor, for ablation of the PTH/PTHrP receptor gene recapitulates the phenotype of PTHrP gene ablation. We have localized PTHrP expression to the embryonic mammary epithelial cells and PTH/PTHrP receptor expression to the mammary mesenchyme using in situ hybridization histochemistry. Finally, we have rescued mammary gland development in PTHrP-null animals by transgenic expression of PTHrP in embryonic mammary epithelial cells. We conclude that PTHrP is a critical epithelial signal received by the mammary mesenchyme and involved in supporting the initiation of branching morphogenesis.
