Nuclear Localization of the Type 1 PTH/PTHrP Receptor in Rat Tissues

Watson, Patricia H.; Fraher, L. J.; Hendy, Geoffrey N.; Chung, Ung‐il; Kisiel, M; Natale, Bryony V.; Hodsman, Anthony B.

doi:10.1359/jbmr.2000.15.6.1033

Cited by 91 publications

(62 citation statements)

References 50 publications

(57 reference statements)

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“…These features allow PTHrP either to be secreted in a paracrine/autocrine fashion or to be retained within the cytosol and to be translocated to the nucleus (4,6,7). Alternative potential mechanisms of PTHrP entry into the cytosol have also been described (8)(9)(10).…”

Section: Ntranuclear Transport Of Numerous Polypeptide Ligands Has mentioning

confidence: 99%

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Miao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

108

113

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Parathyroid hormone (PTH) plays a central role in the regulation of serum calcium and phosphorus homeostasis, while parathyroid hormone-related protein (PTHrP) has important developmental roles. Both peptides signal through the same G protein-coupled receptor, the PTH/PTHrP or PTH type 1 receptor (PTH1R). PTHrP, normally a secreted protein, also contains a nuclear localization signal (NLS) that in vitro imparts functionality to the protein at the level of the nucleus. We investigated this functionality in vivo by introducing a premature termination codon in Pthrp in ES cells and generating mice that express PTHrP (1-84), a truncated form of the protein that is missing the NLS and the C-terminal region of the protein but can still signal through its cell surface receptor. Mice homozygous for the knock-in mutation (Pthrp KI) displayed retarded growth, early senescence, and malnutrition leading postnatally to their rapid demise. Decreased cellular proliferative capacity and increased apoptosis in multiple tissues including bone and bone marrow cells were associated with altered expression and subcellular distribution of the senescenceassociated tumor suppressor proteins p16 INK4a and p21 and the oncogenes Cyclin D, pRb, and Bmi-1. These findings provide in vivo experimental proof that substantiates the biologic relevance of the NLS and C-terminal portion of PTHrP, a polypeptide ligand that signals mainly via a cell surface G protein-coupled receptor.ageing ͉ nucleus ͉ osteoporosis ͉ PTHrP ͉ senescence

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Section: Ntranuclear Transport Of Numerous Polypeptide Ligands Has mentioning

confidence: 99%

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Miao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

108

113

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“…Widespread expression of PTHrP and the PTH/ PTHrP receptor genes and proteins has been found in gut villus epithelium [15,16], suggesting that PTHrP exerts a local regulatory role via an autocrine/paracrine pathway. PTHrP also functions via an intracrine pathway after translocation to the nucleus or nucleolus, and the 88-106 region contains multibasic clusters that have homology to nuclear and nucleolar import signals found in multiple transcription factors [17,18].…”

Section: Introductionmentioning

confidence: 99%

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Shen¹,

Mula²,

Evers³

et al. 2007

Regulatory Peptides

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Parathyroid hormone-related protein (PTHrP) has been localized in human colon cancer tissue and cell lines. We have previously shown that PTHrP increases colon cancer cell proliferation, extracellular matrix adhesion, and cell-surface integrin α6β4 expression. Since cancer cell migration, invasion, and survival are crucial components of metastasis, and colon cancer has a high metastatic potential, in this study we used the human colon cancer cell line LoVo as a model system to study the effects of PTHrP on these parameters. PTHrP expression was modulated by stable transfection with a construct expressing PTHrP (−36 to +139). We report that PTHrP increases cell migration, invasion, and survival. PTHrP altered cell morphology, with PTHrP-overexpressing cells exhibiting increased spreading and several long protrusions. PTHrP also increased the steady-state mRNA levels of the integrin α6 and β4 subunits, indicating a direct and/or indirect effect of PTHrP on the transcriptional and/or posttranscriptional regulation of integrin α6 and β4 expression. Integrin α6β4 activates the phosphoinositol 3-kinase (PI3-K)/Akt pathway, leading to glycogen synthase kinase-3 (GSK-3) deactivation. PTHrP overexpression also led to an increase in active Akt and inactive GSK-3 levels, indicating that the PTHrP-mediated upregulation of integrin α6β4 expression may activate the PI3-K pathway, resulting in increased cell survival, migration and invasion.

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“…The amino acid sequence of the PTH receptor is conserved across species, with PTHR1 cloned from rat osteoblasts displaying 78% conservation to the opossum kidney PTHR1, indicating an important systemic role for the receptor 118 . PTH receptor expression has been identified in a wide array of tissues, including the uterus, gut ovaries, and liver, although expression of the PTHR1 in these tissues is thought to be more important for paracrine/autocrine signaling by the PTH related peptide PTHrP, which also couples to the PTHR1 119 . The highest expression of the PTHR1 within the body is found in the bone and kidney.…”

Section: Part 4: Effect Of Pth On Npt2a Promoter Activitymentioning

confidence: 99%

“…The highest expression of the PTHR1 within the body is found in the bone and kidney. Within the kidney, PTH receptors have been found both in the proximal and distal tubules, as well as the collecting duct 120,121 .…”

Section: Part 4: Effect Of Pth On Npt2a Promoter Activitymentioning

confidence: 99%

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

Murray¹

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PTH is a critical regulator of serum phosphorus. We have previously shown that PTH decreases proximal tubule NpT2a mRNA expression through post‐transcriptional mechanisms, and that this effect can be reproduced by treatment with 8‐bromo‐cAMP, a PKA activator, but not phorbol myristate acetate, a PKC activator. We hypothesize that PKA is the primary mediator of NpT2a mRNA destabilization by PTH. To determine the contribution of each pathway to the PTH response, opossum kidney (OK) cells were treated with selective protein kinase inhibitors in the presence of PTH, and NpT2a mRNA expression was measured by qRT‐PCR. Pretreatment with 10µM PKC inhibitor peptide (PKCi) followed by 100nM PTH for 6h produced a 43.9% decrease in NpT2a mRNA versus PKCi alone. Pretreatment with 10µM H‐89, a PKA inhibitor, prevented the initial decrease in NpT2a mRNA by PTH but did not prevent the ultimate reduction. 8CPT‐2Me‐cAMP, a selective activator of Epac, failed to produce a decrease in NpT2a mRNA after 6h. We conclude that the initial effect of PTH on NpT2a mRNA is PKA‐dependent, whereas chronic regulation involves both the PKA and PKC pathways. Grant Funding Source: Support for this project is provided by VA to EDL.

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Nuclear Localization of the Type 1 PTH/PTHrP Receptor in Rat Tissues

Cited by 91 publications

References 50 publications

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

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