Preproparathyroid Hormone-related Protein, a Secreted Peptide, Is a Substrate for the Ubiquitin Proteolytic System

Meerovitch, Karen; Wing, Simon S.; Goltzman, David

doi:10.1074/jbc.272.10.6706

Cited by 31 publications

(26 citation statements)

References 43 publications

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“…The amino acid sequence of pro-PTHrP, a precursor of PTHrP, can serve as a substrate for the prohormone convertase furine (29). The PTHrP , detected in H295R cells, but not in adrenal tumors, is probably due to ubiquitination and to the proteasome-dependent degradation of the peptide (29,30). PTHrP(1-34) (17 kDa) and other immunoreactive proteins accumulated in H295R cells incubated with a proteasome inhibitor.…”

Section: Pthrp In Adrenocortical Carcinomamentioning

confidence: 99%

Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

Rizk-Rabin

Assié

René-Corail

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Adrenocortical tumors (ACT) are rare and heterogeneous, but their pathogenesis is unclear. The oncoprotein parathyroid hormone -related protein (PTHrP), found in many common tumors, can regulate their growth in an autocrine/paracrine fashion through the PTH-R1 receptor. Little is known about the role of PTHrP in ACT. We monitored the synthesis of PTHrP and PTH-R1 in a series of 25 ACT: 12 adrenocortical carcinomas (ACC) and 13 adrenocortical adenomas (ACA), and investigated the effects of PTHrP (1-

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Section: Pthrp In Adrenocortical Carcinomamentioning

confidence: 99%

Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

Rizk-Rabin

Assié

René-Corail

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Plasmid pcDNA3.1/His-IRP2 was linearized by XbaI and in vitro translated with a TNT-coupled wheat germ kit (Promega) in the presence of [ 35 S]methionine. Assays of ubiquitin conjugation and degradation were performed as previously described (34).…”

Section: Methodsmentioning

confidence: 99%

S-Nitrosylation of IRP2 Regulates Its Stability via the Ubiquitin-Proteasome Pathway

Kim

Wing

Ponka

2004

Molecular and Cellular Biology

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Nitric oxide (NO) is an important signaling molecule that interacts with different targets depending on its redox state. NO can interact with thiol groups resulting in S-nitrosylation of proteins, but the functional implications of this modification are not yet fully understood. We have reported that treatment of RAW 264.7 cells with NO caused a decrease in levels of iron regulatory protein 2 (IRP2), which binds to iron-responsive elements present in untranslated regions of mRNAs for several proteins involved in iron metabolism. In this study, we show that NO causes S-nitrosylation of IRP2, both in vitro and in vivo, and this modification leads to IRP2 ubiquitination followed by its degradation in the proteasome. Moreover, mutation of one cysteine (C178S) prevents NO-mediated degradation of IRP2. Hence, S-nitrosylation is a novel signal for IRP2 degradation via the ubiquitin-proteasome pathway.Physiologically, the majority of cells in vertebrates acquire iron from a well-characterized plasma glycoprotein, transferrin (Tf). Iron uptake from Tf involves the binding of Tf to the Tf receptors (TfR), internalization of Tf within an endocytic vesicle by receptor-mediated endocytosis, and the release of iron from Tf by a decrease in endosomal pH (15,39,41). Following iron release from Tf within endosomes, Fe 2ϩ passes through the endosomal membrane by divalent metal transporter 1 (2, 8) and then enters the poorly characterized intracellular labile pool (LIP). Intracellular iron that exceeds the requirement for the synthesis of functional heme and nonheme iron-containing proteins is stored within ferritin (39, 41).In general, cellular iron homeostasis is regulated posttranscriptionally by the cytoplasmic factors iron regulatory proteins 1 and 2 (IRP1 and IRP2), which "sense" iron levels in the LIP (7,14,35,41). In the absence of iron in the LIP, IRPs bind to specific nucleotide sequences called iron-responsive elements (IREs), which are located in the 3Ј untranslated region of TfR mRNA (36, 41) and the 5Ј untranslated region of ferritin mRNA (14,30,41). The binding of IRPs to IREs stabilizes TfR mRNA and blocks ferritin mRNA translation. In ironreplete cells, IRP1 contains a [4Fe-4S] cluster and binds RNA with low affinity (13, 41). IRP2, however, does not have the iron-sulfur cluster and is degraded under iron-replete conditions. This degradation is dependent on a 73-amino-acid insertion, rich in cysteine, which is absent in IRP1 (11,20). Hence, the expansion of the LIP inactivates IRP1 binding to IREs and leads to a degradation of IRP2, resulting in a rapid degradation of TfR mRNA and an efficient translation of ferritin mRNA (7,35,41). Importantly, IRPs can also be affected by various forms of oxidative stress and nitric oxide (NO) (6,12,15,38,40,46).NO is an important signaling molecule (17, 18) that interacts with different targets depending on its redox state. The reduced form of NO (the notation NO is used here as a generic expression encompassing all nitrogen monoxide species), NO ⅐ , interacts mainly with iron ...

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“…PTHrP is synthesized as a prepro protein that encodes a mature 141-amino acid protein (in the rat) that is post-translationally cleaved to generate the bioactive peptide 1-36 as well as other poorly characterized fragments. While studying the post-translational regulation of PTHrP, we showed that full-length endogenously overexpressed PTHrP was degraded by the ubiquitin-dependent proteolytic system (16). The ubiquitin proteolytic pathway is responsible for the degradation of misfolded or aberrant polypeptides in the cytosol and nucleus (17).…”

mentioning

confidence: 99%

Proparathyroid Hormone-related Protein Is Associated with the Chaperone Protein BiP and Undergoes Proteasome-mediated Degradation

Meerovitch

Wing

Goltzman

1998

Journal of Biological Chemistry

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Parathyroid hormone-related peptide (PTHrP) is an important causal factor for hypercalcemia associated with malignancy. In addition to the endocrine functions attributed to secretory forms of the peptide, PTHrP also plays a local role as a mediator of cellular growth and differentiation presumably at least in part through intracellular pathways. In studying the post-translational regulation of PTHrP, we observed that PTHrP was conjugated to multiple ubiquitin moieties. We report here that the proteasome is responsible for the degradation of the endoplasmic reticulum-associated precursor, proPTHrP. Cells expressing prepro-PTHrP and exposed to lactacystin accumulate pro-PTHrP assessed by anti-pro specific antibodies. Brefeldin A-treated cells also accumulate pro-PTHrP suggesting that degradation does not occur in the endoplasmic reticulum (ER) lumen. Subcellular fractionation of both lactacystin and brefeldin Atreated cells indicated that accumulated pro-PTHrP resides in microsomal fractions with a portion of the protein exposed to the cytosolic side of the ER membrane as assessed by protease protection experiments. Immunoprecipitation and Western blot analysis identified pro-PTHrP in association with the ER molecular chaperone protein BiP. We conclude that pro-PTHrP from the ER can gain access to the cytoplasmic side of the ER membrane where it can undergo ubiquitination and degradation by the proteasome.Parathyroid hormone-related protein (PTHrP)

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Preproparathyroid Hormone-related Protein, a Secreted Peptide, Is a Substrate for the Ubiquitin Proteolytic System

Cited by 31 publications

References 43 publications

Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

S-Nitrosylation of IRP2 Regulates Its Stability via the Ubiquitin-Proteasome Pathway

Proparathyroid Hormone-related Protein Is Associated with the Chaperone Protein BiP and Undergoes Proteasome-mediated Degradation

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