The nucleus: A target site for parathyroid hormone-related peptide (PTHrP) action

Nguyen, Matthew; Karaplis, Andrew C.

doi:10.1002/(sici)1097-4644(19980801)70:2<193::aid-jcb5>3.0.co;2-j

Cited by 56 publications

(39 citation statements)

References 37 publications

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“…In this model, PTHrP secretion results from trafficking of the precursor to the endoplasmic reticulum directed by a typical signal peptide. [3][4][5][6] In addition to this typical neuroendocrine trafficking and secretion, PTHrP is unusual in that it is also able to traffic to the nucleus of multiple cells [7][8][9][10][11][12][13][14] (Figure 1). This "bidirectional trafficking" results from the presence in the PTHrP sequence of alternate translational initiation sites, 1 of which uses an AUG translational initiation codon directly upstream of the signal peptide, as well as a second functional CUG translational initiation codon, which is internal to, and therefore disrupts, the signal peptide.…”

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confidence: 99%

Cellular Mechanism Through Which Parathyroid Hormone–Related Protein Induces Proliferation in Arterial Smooth Muscle Cells

Fiaschi-Taesch

Sicari

Ubriani

et al. 2006

Circulation Research

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Abstract-Parathyroid hormone-related protein (PTHrP) is present in vascular smooth muscle (VSM), is markedly upregulated in response to arterial injury, is essential for normal VSM proliferation, and also markedly accentuates neointima formation following rat carotid angioplasty. PTHrP contains a nuclear localization signal (NLS) through which it enters the nucleus and leads to marked increases in retinoblastoma protein (pRb) phosphorylation and cell cycle progression. Our goal was to define key cell cycle molecules upstream of pRb that mediate cell cycle acceleration induced by PTHrP. The cyclin D/cdk-4,-6 system and its upstream regulators, the inhibitory kinases (INKs), are not appreciably influenced by PTHrP. In striking contrast, cyclin E/cdk-2 kinase activity is markedly increased by PTHrP, and this is a result of a specific, marked, PTHrP-induced proteasomal degradation of p27 kip1 . Adenoviral restoration of p27 kip1 fully reverses PTHrP-induced cell cycle progression, indicating that PTHrP mediates its cell cycle acceleration in VSM via p27 kip1 . In confirmation, adenoviral delivery of PTHrP to murine primary vascular smooth muscle cells (VSMCs) significantly decreases p27 kip1 expression and accelerates cell cycle progression. p27 kip1 is well known to be a central cell cycle regulatory molecule involved in both normal and pathological VSM proliferation and is a target of widely used drug-eluting stents. The current observations define a novel "PTHrP/p27 kip1 pathway" in the arterial wall and suggest that this pathway is important in normal arterial biology and a potential target for therapeutic manipulation of the arterial response to injury. Key Words: cell cycle progression Ⅲ p27Kip1/pRb Ⅲ proliferation Ⅲ PTHrP Ⅲ vascular smooth muscle cell proliferation P arathyroid hormone-related protein (PTHrP) was originally identified through the search for the humoral factor responsible for humoral hypercalcemia of malignancy.

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confidence: 99%

Cellular Mechanism Through Which Parathyroid Hormone–Related Protein Induces Proliferation in Arterial Smooth Muscle Cells

Fiaschi-Taesch

Sicari

Ubriani

et al. 2006

Circulation Research

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“…PTHrP may modulate cellular function in a dual mode of action: ®rst, by binding and activating its cognate cell surface Gprotein-coupled receptor and, second, by direct intracellular eects following translocation to the nucleus and/or nucleolus of the target cell. 5 PTHrP can be secreted by either the regulated secretory pathway, or the constitutive secretory pathway. The cellular response to PTHrP-nuclear interaction is cell- PTHrP has been implicated as an autocrine modulator of growth and dierentiation in the colon.…”

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confidence: 99%

Immunohistochemical study of parathyroid hormone-related protein in vesical transitional epithelium of patients with spinal cord injury

et al. 1999

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Introduction: Parathyroid hormone-related protein (PTHrP), in addition to the wellestablished role in endochrondral bone development, is believed to be an important mediator of cellular growth and dierentiation in a number of non-bony tissues. Objectives: To compare the immunohistochemical staining of vesical transitional epithelium to antibodies raised to synthetic peptides of PTHrP composed of amino acid sequences 43 ± 52 and 127 ± 138 in patients with spinal cord injury (SCI) and neuropathic bladder (n=14), and control patients with intact neuraxis and no history of bladder cancer (n=10). Setting: Male SCI patients registered with Regional Spinal Injuries Centre, Southport, England. Intervention: Endoscopic cold cup biopsy from the trigone of the urinary bladder was taken from patients with SCI while they were undergoing a therapeutic procedure in the urinary bladder. The control samples of bladder biopsies were taken from the archives of the Department of Histopathology, District General Hospital, Southport. Immunohistochemistry was performed using rabbit antibodies raised against synthetic peptides of human PTHrP (43 ± 52) and PTHrP (127 ± 138). The biopsies were examined for immunostaining of transitional epithelium. Results: Of the 14 biopsies of SCI patients, positive immunostaining using antibodies to both the PTHrP peptides was found in four cases; ®ve biopsies showed positive immunostaining only to anti-PTHrP (43 ± 52); and ®ve biopsies showed no immunostaining with either of the PTHrP peptides. In contrast, transitional epithelium in the biopsy specimens of ten control subjects with no history of bladder cancer showed no immunostaining with either of the PTHrP peptides. Conclusion: This study revealed that the transitional epithelium of neuropathic urinary bladder exhibits increased predilection for positive immunohistochemical staining for PTHrP (43 ± 52), and to a lesser extent, to PTHrP (127 ± 138), as compared to the vesical transitional epithelium of able bodied individuals with no history of vesical malignancy. The possible role of PTHrP in the cellular dierentiation of urothelium of neuropathic bladder, and thereby, in the pathogenesis of cystitis in SCI patients, needs to be explored.

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“…Subsequent research has identified several normal physiological actions including growth and development, calcium homeostasis and smooth muscle relaxation (Wysolmerski and Broadus, 1994). Parathyroid hormone-related protein acts locally in an autocrine, paracrine or intracrine manner (Broadus et al, 1985;Burtis et al, 1987;Suva et al, 1987) with intracrine activity being the result of translocation to the nucleus, mediated by a bipartite nuclear localisation sequence (NLS) within the mid-region of the PTHrP peptide (Nguyen and Karaplis, 1998). Nuclear-localised PTHrP has been shown to be both mitogenic and antiapoptotic (Aarts et al, 2001;.…”

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PTHrP increases transcriptional activity of the integrin subunit α5

2007

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Increasing evidence is emerging highlighting the role of parathyroid hormone-related protein (PTHrP) during metastasis by regulating cell adhesion. The current study demonstrated that modulation of PTHrP expression by PTHrP overexpression and small interfering RNA-induced silencing resulted in changes in cell adhesion and integrin expression. RNA interference of endogenous PTHrP caused a significant reduction in cell adhesion of a breast cancer cell line to collagen type I, fibronectin and laminin (Po0.05) and of a colon cancer cell to collagen type I and fibronectin (Po0.05). Overexpression of PTHrP induced a significant increase in cell adhesion of colon (Po0.0001) and breast (Po0.05) cancer cells to the same extracellular matrix proteins. These PTHrP-mediated effects were attributed to changes in integrin expression as the differences in adhesion profile correlated with the integrin expression profile. In an attempt to elucidate the mechanism whereby PTHrP regulates integrin expression, promoter activity of the integrin a 5 subunit was analysed and significant increases in transcriptional activity were observed in PTHrP overexpressing cells (Po0.0001), which was dependent on nuclear localisation. These results indicate that modulation of cell adhesion is a normal physiological action of PTHrP, mediated by increasing integrin gene transcription.

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The nucleus: A target site for parathyroid hormone-related peptide (PTHrP) action

Cited by 56 publications

References 37 publications

Cellular Mechanism Through Which Parathyroid Hormone–Related Protein Induces Proliferation in Arterial Smooth Muscle Cells

Cellular Mechanism Through Which Parathyroid Hormone–Related Protein Induces Proliferation in Arterial Smooth Muscle Cells

Immunohistochemical study of parathyroid hormone-related protein in vesical transitional epithelium of patients with spinal cord injury

PTHrP increases transcriptional activity of the integrin subunit α5

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