Prohormone convertase 1 (PC1) processing and sorting: effect of PC1 propeptide and proSAAS

Lee, Sang-Nam; Prodhomme, Emmanuel; Lindberg, Iris

doi:10.1677/joe.0.1820353

Cited by 34 publications

(24 citation statements)

References 53 publications

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“…9). PC1/3, the cleavage enzyme that produces ACTH and α-MSH from POMC, is activated by proteolytic cleavage of its C-terminal tail (Lee, et al 2004). We were able to detect the expression of the partially active 84 kD and the inactive 97 kD form in aortic mesenchymal progenitors and the highly active 66 kD form of PC1/3 in the murine macrophage (Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Evans

Fernando

Ragolia

2012

Molecular and Cellular Endocrinology

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A local melanocortin system is active during tissue injury and inflammation. Thus far this system has been described as autocrine in nature where local production of pro-opiomelanocortin (POMC) peptides by leukocytes feeds back on melanocortin receptor (MC-R) expressing immune cells to quell inflammatory cytokine production. Here we present evidence that POMC peptides may generate extracellular matrix (ECM) changes by inducing matrix production by cells of the mesenchymal lineage through activation of the MC2-R. Using immunoblot, we determined that mouse aorta-derived mesenchymal progenitor cells express both MC2-R and MC3-R. These progenitors respond to treatment with ACTH by increasing collagen matrix synthesis as assessed by picrosirius red stain and 3H-proline incorporation. ACTH also induces transient increases in intracellular calcium ([Ca2+]i) as assessed using the fluorescent Ca2+ indicator, fura- 2. The ACTH-induced changes in [Ca2+]i are consistent with MC2-R signaling and consist of both an intracellular release and an extracellular influx of Ca2+. Both mouse aortic mesenchymal progenitors and mouse macrophage cells express POMC and the prohormone convertase 1/3 (PC1/3) indicating they have the potential to contribute to the local production of POMC peptides. These data demonstrate functional MC2-R expression in mouse aorta-derived mesenchymal progenitors and implicate both macrophage and mesenchymal cells as relevant sources of local POMC peptides.

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Section: Resultsmentioning

confidence: 99%

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Evans

Fernando

Ragolia

2012

Molecular and Cellular Endocrinology

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“…However, the dominant inheritance did not result in the full scope of endocrinopathies associated with PC1/3 null patients, confirming residual PC1/3 activity. As described above, the inhibitory function of PC1/3 prodomain was already established in vitro (54,56,57). The earlier described PCSK1-p.G209R mutant which was shown to retain the PCSK1-p.P258T hypomorph in the ER, could have a similar limited dominant negative effect (89).…”

Section: B Heterozygous Mutations Contribute To Obesitymentioning

confidence: 99%

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

et al. 2016

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Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

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“…Evaluation of treatments over the long term will determine whether the beneficial effects of PCSK9 inhibition on LDL-C levels will directly translate into coronary artery disease risk reduction [70][71][72] . Chen et al [72] identified PCSK9 as a specific SEC24A-dependent COPII cargo: indeed as trans-membrane and soluble proteins co-translationally inserted into the endoplasmic reticulum (ER), it is packaged into transport vesicles coated with coat protein complex Ⅱ (COPⅡ) for the export from the ER and the delivery to the Golgi for further processing [73] . Chen et al [72] reported that complete deficiency of SEC24A is compatible with normal development and survival in mice.…”

Section: Inhibition Of Pcsk9mentioning

confidence: 99%

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

Trapani

Segatto

Pallottini

2013

WJH

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Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of dyslipidemia.© 2013 Baishideng Publishing Group Co., Limited. All rights reserved. Key words: Aging; Cholesterol; HypercholesterolemiaCore tip: The strategies used to reduce plasma cholesterol levels in elderly people are mainly addressed to the inhibition of the rate limiting enzyme of cholesterol biosynthetic pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), in order to increase low density lipoprotein (LDL) receptor membrane exposure and LDL clearance from the circulation. Indeed current therapies are mostly based on the prescription of statins (HMGR inhibitors) that are pretty effective but that exert side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to elderly. Thus, new therapeutic agents should be taken into account.Trapani L, Segatto M, Pallottini V. New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid

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Prohormone convertase 1 (PC1) processing and sorting: effect of PC1 propeptide and proSAAS

Cited by 34 publications

References 53 publications

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

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