Stimulation of Protein Kinase C Activity in Cells Expressing Human Parathyroid Hormone Receptors by C- and N-Terminally Truncated Fragments of Parathyroid Hormone 1–34

Whitfield, J. F.; Isaacs, Richard; Chakravarthy, Balu; MacLean, Susanne; Morley, Paul; Willick, Gordon E.; Divieti, P.; Bringhurst, F. Richard

doi:10.1359/jbmr.2001.16.3.441

Cited by 30 publications

(14 citation statements)

References 41 publications

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“…The osteogenic activity of a C terminus-truncated PTH analogue, hPTH-(1-31)NH 2 (19), is similar to that of the well studied PTH-(1-34) (20). This analogue has a helix-bend-helix structure in aqueous media at near-physiological pH and ionic strength (14), similar to that found in previous studies of PTH-(1-34) (13).…”

supporting

confidence: 79%

“…We should emphasize that side-chain substitution and methylation at the site of a particular residue need not give similar effects on binding and activity. For example, there is a high degree of stringency for the Arg 20 side chain (46), but methylation of the Arg 20 ␣-amino group has relatively little effect on binding and signaling activity in comparison to other residues, such as Glu 22 , which can be substituted more freely.…”

Section: Discussionmentioning

confidence: 99%

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Backbone-methylated Analogues of the Principle Receptor Binding Region of Human Parathyroid Hormone

Barbier

Gardella

Dean

et al. 2005

Journal of Biological Chemistry

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We have used backbone N-methylations of parathyroid hormone (PTH) to study the role of these NH groups in the C-terminal amphiphilic ␣-helix of PTH (1-31) in binding to and activating the PTH receptor (P1R). The circular dichroism (CD) spectra indicated the structure of the C-terminal ␣-helix was locally disrupted around the methylation site. The CD spectra differences were explained by assuming a helix disruption for four residues on each side of the site of methylation and taking into account the known dependence of CD on the length of an ␣-helix. Binding and adenylyl cyclase-stimulating data showed that outside of the ␣-helix, methylation of residues Asp 30 and Val 31 had little effect on structure or activities. Within the ␣-helix, disruption of the structure was associated with increased loss of activity, but for specific residues Val 21 , Leu 24 , Arg 25 , and Leu 28 there was a dramatic loss of activities, thus suggesting a more direct role of these NH groups in correct P1R binding and activation. Activity analyses with P1R-delNT, a mutant with its long N-terminal region deleted, gave a different pattern of effects and implicated Ser 17 , Trp 23 , and Lys 26 as important for its PTH activation. These two groups of residues are located on opposite sides of the helix. These results are compatible with the C-terminal helix binding to both the N-terminal segment and also to the looped-out extracellular region. These data thus provide direct evidence for important roles of the C-terminal domain of PTH in determining high affinity binding and activation of the P1R receptor.

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supporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Backbone-methylated Analogues of the Principle Receptor Binding Region of Human Parathyroid Hormone

Barbier

Gardella

Dean

et al. 2005

Journal of Biological Chemistry

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“…In Pthrp-ablated animals, primary tumor hyperplasia wa.s considerably delayed, and palpable tumors appeared much later and were smaller and fewer than in control mice. fl: ing high PTHrP levels presented higher rates of metastasis and increased or earlier morrality (40)(41)(42)(43). A recent report reached opposite conclusions, but relied on animal models with a very late-onset oncogenic system (neu based), which is more relevant to tumors arising in older animals (44), and used mice with a heterogeneous genet· ic background.…”

Section: Discussionmentioning

confidence: 99%

Osteoblast-Derived PTHRP and Breast Cancer Bone Metastasis

Karaplis¹

2004

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE November 2004 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES). McGill University Montreal, Canada H3A2T5 Metastases to bone, l ur:g, and other organs are common and catastrophic consequences of breast cancer progression. There is therefore an urgent need to improve current therapies I that address cancer grm.,th and spread. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)UParathyroid hormone-related protein (PTHrP, also referred to as parathyroid hormone-like protein [PTHLP]) is a secreted factor expressed in almost all normal fetal and adult tissues, acting as an autocrine, paracrine, or intracrine factor in a wide range of developmental and physiological processes. Although PTHrP's dysregulated expression has traditionally been associated with oncogenic pathologies as the major causative agent of malignancy-associated hypercalcemia, recent evidence revealed a driving role in skeletal metastasis progression. Here, we demonstrate that PTHrP is also closely involved in breast cancer initiation, growth and metastasis to bone and lung through mechanisms separate from its bone turnover action, and we suggest that PTHrP as facilitator of oncogenes could serve as a novel target for therapeutic intervention. SUBJECT TERMS INTRODUCTIONParathyroid hormone-related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancyassociated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its involvement in tumor initiation and metastasis in vivo is not clear. BODYPTHrP is expressed in normal epithelial cells but its expression increases in breast cancer and becomes associated with multiple metastatic lesions and reduced survival. It is, however, still unknown whether PTHrP overexpression is simply a con...

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“…NHERF-1 has also been found to be important not only in the formation of the apical membrane signalosomes, but also for modulating the amount of cAMP generated in response to PTH stimulation, and its presence is mandatory for cAMP inhibition of NHE3 50,132 . activation of PKC, the PTHR1s expressed in human, mouse, and opossum kidneys are also capable of activating PKC through PLC-independent mechanisms 135 .…”

Section: Pth-induced Pka Signalingmentioning

confidence: 99%

“…OK cells were treated with 100nM PTH(1-31) to selectively activate PKA, or 1μM PTH(3-34) to selectively activate PKC, for up to 8h. The concentration used for PTH(1-31) was determined according to concentrations published in previous studies 135 , while the optimal concentration for PTH(3-34) was determined by performing dose response curves of stimulated PKA activity and selecting the concentration at which PKA activity showed the least increase. PKA and PKC activity assays were performed to confirm the selective pathway-activating properties of each analogue.…”

Section: Part 1: Effects Of Pth Analogues On Npt2a Mrna Expressionmentioning

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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Stimulation of Protein Kinase C Activity in Cells Expressing Human Parathyroid Hormone Receptors by C- and N-Terminally Truncated Fragments of Parathyroid Hormone 1–34

Abstract: ABSTRACT

Cited by 30 publications

References 41 publications

Backbone-methylated Analogues of the Principle Receptor Binding Region of Human Parathyroid Hormone

Backbone-methylated Analogues of the Principle Receptor Binding Region of Human Parathyroid Hormone

Osteoblast-Derived PTHRP and Breast Cancer Bone Metastasis

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

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