C-terminal fragment of parathyroid hormone-related protein, PTHrP-(107-111), stimulates membrane-associated protein kinase C activity and modulates the proliferation of human and murine skin keratinocytes

Whitfield, J. F.; Isaacs, Richard; Jouishomme, Hervé; MacLean, Susanne; Chakravarthy, Balu; Morley, Paul; Barisoni, D.; Regalia, E.; Armato, Ubaldo

doi:10.1002/(sici)1097-4652(199601)166:1<1::aid-jcp1>3.0.co;2-t

Cited by 39 publications

(27 citation statements)

References 59 publications

(50 reference statements)

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“…3 In addition to its role in the induction of HHM, PTHrP has been shown to be involved in the regulation of cell proliferation and apoptosis in a wide variety of normal and neoplastic tissues. [4][5][6][7][8][9][10][11][12][13][14][15] The human PTHrP gene is composed of nine exons spanning more than 15 kilobases of genomic DNA and 15 different transcripts can be generated by alternative splicing of the 5 0 and 3 0 exons. Nevertheless, all PTHrP transcripts share products of exons 5 and 6 that encode for the prepro region and the majority of the mature peptide.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma

et al. 2005

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Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy seen in the majority of adult T-cell leukemia/lymphoma (ATLL) patients with human T-cell lymphotropic virus type-1 (HTLV-1) infection. HTLV-1 Tax has been shown to complex with ETS-1 and SP1 to transactivate the PTHrP P3 promoter. Previously, we established a SCID/bg mouse model of human ATL with RV-ATL cells and showed that PTHrP expression was independent of Tax. In this study, we report an inverse correlation of PTHrP with tax/rex mRNA in multiple HTLV-1-positive cell lines and RV-ATL cells. Stimulation of Jurkat T cells with PMA/ionomycin upregulated the PTHrP P3 promoter by a previously characterized Ets binding site and also induced protein/DNA complex formation identical to that observed in RV-ATL cells. Further, we provide evidence that cotransfection with Ets-1 and constitutively active Mek-1 in HTLV-1-negative transformed T cells with stimulation by PMA/ionomycin not only resulted in a robust induction of PTHrP P3 but also formed a complex with ETS-1/P3 EBS similar to that in ATLL cells. Our data demonstrate that transcriptional regulation of PTHrP in ATLL cells can be controlled by T-cell receptor signaling and the ETS and MAPK ERK pathway in a Tax-independent manner.

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Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma

et al. 2005

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“…The swollen cells were then scraped off the dish with a rubber policeman, lysed by vigorous vortexing for 2 minutes, and then centrifuged at 1,000g at 4°C for 15 minutes to pellet and discard nuclei and unlysed cells, followed by centrifugation at 100,000g for 30 minutes at 4°C (31). We collected the resulting supernatant, which contained the cytosol, as well as other proteins released from organelles by the described cell lysis procedure, and termed this the "intracellular" fraction.…”

Section: Methodsmentioning

confidence: 99%

Errata

1999

Arthritis & Rheumatism

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Objective. Increased nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity in chondrocytes is associated with cartilage matrix inorganic pyrophosphate (PPi) supersaturation in chondrocalcinosis.This study compared the roles of the transforming growth factor ␤ (TGF␤)-inducible plasma cell membrane glycoprotein-1 (PC-1) and the closely related B10 NTPPPH activities in chondrocyte PPi metabolism.Methods. NTPPPH expression was studied using reverse transcriptase-polymerase chain reaction and Western blotting. Transmembrane PC-1 (tmPC-1), water-soluble secretory PC-1 (secPC-1), and transmembrane B10 were expressed by adenoviral gene transfer or plasmid transfection, and expression of PPi was assessed in cultured articular chondrocytes and immor- talized NTPPPH-deficient costal chondrocytes (TC28 cells).Results. PC-1 and B10 messenger RNA were demonstrated in articular cartilages in situ, in untreated cultured normal articular chondrocytes, and in TC28 cells. Expression of tmPC-1 and secPC-1, but not B10, rendered the NTPPPH-deficient TC28 cells able to increase expression of extracellular PPi, with or without addition of TGF␤ (10 ng/ml) to the media. More plasma membrane NTPPPH activity was detected in cells transfected with tmPC-1 than in cells transfected with B10. Furthermore, confocal microscopy with immunofluorescent staining of articular chondrocytes confirmed preferential plasma membrane localization of PC-1, relative to B10. Finally, both PC-1 and B10 increased the levels of intracellular PPi, but PC-1 and B10 appeared to act principally in different intracellular compartments (Golgi and post-Golgi versus pre-Golgi, respectively).Conclusion. PC-1 and B10 NTPPPH activities were not redundant in chondrocytes. Although increased PC-1 and B10 expression caused elevations in intracellular PPi, the major effects of PC-1 and B10 were exerted in distinct subcellular compartments. Moreover, PC-1 (transmembrane and secreted), but not B10, increased the levels of extracellular PPi. Differential expression of PC-1 and B10 could modulate cartilage mineralization in degenerative joint diseases.Articular cartilage chondrocytes have the unique ability to constitutively elaborate relatively large amounts of extracellular inorganic pyrophosphate (PPi), and cartilage is the major source of free PPi in joints (1-3). Moreover, in aging and osteoarthritic (OA) articular cartilage, a dysregulated increase in PPi elaboration in chondrocytes and other changes in the chondrocyte differentiation and matrix composition promote calcium Ms Moffa'

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“…The 107-111 region was selected for deletion because it is extremely highly conserved among mammalian species, in contrast to the 112-139 region, which is less well conserved. [3][4][5][21][22][23][24][25] The other regions (112-120, 121-130, and 131-139) were selected randomly for deletion, because there is no known functional significance of these segments. Surprisingly, as shown in Figure 2B, despite its intense evolutionary conservation, deletion of the 107-111 region had no adverse effect on proliferation.…”

Section: Retinoblastoma Protein Prb Is Constitutively Phosphorylatementioning

confidence: 99%

“…These serine/threonine residues presumably serve as sites for posttranslational modification, such as phosphorylation or acylation. The location of the key amino acids came as a surprise, for we had anticipated that the PTHrP(107-111) region, which is intensely conserved among species, [3][4][5][21][22][23][24][25] would prove to be essential for proliferation. Presumably, this conserved region plays a role distinct from those explored here.…”

Section: C-terminal Mapping Of Pthrpmentioning

confidence: 99%

Parathyroid Hormone–Related Protein as a Regulator of pRb and the Cell Cycle in Arterial Smooth Muscle

et al. 2004

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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 G 2 /M phases of the cell cycle. These effects require critical serine and threonine residues at positions Ser 119 , Ser 130 , Thr 132 , and Ser 138 in the carboxy-terminus of PTHrP and are associated with the phosphorylation of the key cell cycle checkpoint regulator retinoblastoma protein, pRb. Second, because PTHrP devoid of the NLS serves as an inhibitor of VSM proliferation, we hypothesized that local delivery of NLS-deleted PTHrP to the arterial wall at the time of angioplasty might prevent neointimal hyperplasia. As hypothesized, using a rat carotid angioplasty model, adenoviral delivery of NLS-deleted PTHrP completely abolished the development of the neointima after angioplasty. Conclusions-PTHrP

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C-terminal fragment of parathyroid hormone-related protein, PTHrP-(107-111), stimulates membrane-associated protein kinase C activity and modulates the proliferation of human and murine skin keratinocytes

Cited by 39 publications

References 59 publications

Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma

Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma

Errata

Parathyroid Hormone–Related Protein as a Regulator of pRb and the Cell Cycle in Arterial Smooth Muscle

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