Apolipoprotein E Inhibits Serum-stimulated Cell Proliferation and Enhances Serum-independent Cell Proliferation

Ho, Yu‐Ling; Deckelbaum, Richard J.; Chen, Yachi; Vogel, Thomas; Talmage, David A.

doi:10.1074/jbc.m105325200

Cited by 23 publications

(12 citation statements)

References 34 publications

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“…More relevant, LRP (next to ApoER2 and megalin) is a critical receptor for apoE, whose allelic status is a major risk factor for late-onset Alzheimer's disease (AD) (35) and other neurodegenerative disorders. Consistently, apoE-mediated functional modulation (potentially via agonistic binding of lipoprotein receptors) of cellular responses to mitogens as well as apoE-mediated inhibition of cell proliferation has been described (36). Recent work in mice also established LRP6 as critical co-receptor for WNT signal transduction (37,38,39) known to mediate cell differentiation, cell polarity, and cell adhesion.…”

Section: Discussionmentioning

confidence: 73%

Evidence of Functional Modulation of the MEKK/JNK/cJun Signaling Cascade by the Low Density Lipoprotein Receptor-related Protein (LRP)

Lutz

Nimpf

Jenny

et al. 2002

Journal of Biological Chemistry

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Lipoprotein receptors, such as LRP, have been shown to assemble multiprotein complexes containing intracellular signaling molecules; however, in vivo, their signaling function is poorly understood. Using a novel LRP receptor fusion construct, a type I transmembrane protein chimera, termed sIgG-LRP (bearing the intracellular COOH-terminal tail of human LRP as recombinant fusion to a transmembrane region plus the extracellular IgG-F c domain), we here investigated LRP signal transduction specificity in intact cells. First and similar to activated ␣2-macroglobulin as agonist of endogenous LRP, expression of sIgG-LRP demonstrated significant apoptosis protection. Second and similar to ␣2-macroglobulin-induced endogenous LRP, sIgG-LRP is sufficient to negatively modulate mitogen-induced Elk-1 and cJun (but not NF-B) transcriptional activity. Third, expression of sIgG-LRP also impaired cJun transactivation mediated by constitutive active mutants of Rac-1 and MEKK-1. Fourth and unexpectedly, sIgG-LRP expression was found to be associated with a marked enhancement of mitogen-induced cJun amino-terminal kinase (JNK) activation. Fifth, confocal microscopic examination and subcellular fractionation demonstrated that sIgG-LRP and JNK co-localize in transfected cells. Therefore, sIgG-LRP expression was found to significantly impair activation-induced translocation of JNK into the nucleus. Taken together, we here demonstrate that sIgG-LRP protein sequesters activated JNK into the plasma membrane compartment in intact cells, inhibiting nuclear activation of the JNK-dependent transcription factors Elk-1 and cJun. Low density lipoprotein receptor-related protein (LRP)1 is one member of the LDL receptor family that also includes the LDL receptor, the very low density lipoprotein receptor, megalin, LRP5, LRP6, and apoER2 receptor (see Ref. 1 LRP is expressed abundantly in neurons and microglia of the central nervous system (3, 4). Disruption of the LRP gene in mice blocks development of LRP Ϫ/Ϫ embryos around the implantation (5). However, the complex phenotype of the few malformed LRP-deficient embryos that survive until E10 (6), similar to the very low density lipoprotein ApoER2 receptor double knockout phenotype (7), postulated some LRP receptor signaling function(s). Consistently, LRP and several of its ligands, including ␣2-macroglobulin, tissue plasminogen activator (tPA), apoE-containing lipoproteins, and the amyloid precursor protein (APP) (8, 9), have been implicated in various cellular functions including the neuropathogenesis of Alzheimer's disease (see Ref. 10 for review).Based on yeast two-hybrid and co-immunoprecipitation analysis, lipoprotein receptors assemble intracellular multiprotein complexes containing the adapter and scaffold proteins Dab-1 (7), FE65 (11) and Shc (12, 13), the non receptor tyrosine kinases Src and Fyn (14), and the JNK-interacting proteins (JIP-1 & 2) (15, 16), which act as molecular scaffolds for the JNK signaling pathway (see Ref. 17 for review). Quite similarly, such intracellular signali...

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Section: Discussionmentioning

confidence: 73%

Evidence of Functional Modulation of the MEKK/JNK/cJun Signaling Cascade by the Low Density Lipoprotein Receptor-related Protein (LRP)

Lutz

Nimpf

Jenny

et al. 2002

Journal of Biological Chemistry

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“…Apolipoprotein E can be produced in macrophages [20]. In a glioblastoma study, ApoE from macrophages was shown to be involved in the delivery of lipids to tumor cells and in the recycling of lipids by macrophages in necrotic areas [21].…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E expression promotes lung adenocarcinoma proliferation and migration and as a potential survival marker in lung cancer

Chen

Lai

et al. 2011

Lung Cancer

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“…Traditional approaches to this problem have limitations and rely on simple qualitative assessments. Traditional methodologies that have been used to study macrophage apoE include characterizing the tissue distribution of apoE (11), measuring the effects of the endogenous synthesis of apoE vs. its complete absence (11), and measuring the effects of the endogenous synthesis vs. exogenous application of apoE (15,19). These methods are useful in comparative assessments, but they are unable to simultaneously quantify the serial effects mediated by apoE or other secreted biological mediators.…”

Section: Discussionmentioning

confidence: 99%

ApoE-mediated cholesterol efflux from macrophages: separation of autocrine and paracrine effects

Dove¹,

Linton²,

Fazio³

2005

American Journal of Physiology-Cell Physiology

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mediated cholesterol efflux from macrophages: separation of autocrine and paracrine effects. Am J Physiol Cell Physiol 288: C586 -C592, 2005. First published October 27, 2004 doi:10.1152/ajpcell. 00210.2004.-Macrophages in the vessel wall secrete high levels of apolipoprotein E (apoE). Cholesterol efflux from macrophages to apoE has been shown to decrease foam cell formation and prevent atherosclerosis. An apoE molecule can mediate cholesterol efflux from the macrophage that originally secreted it (autocrine effect) or from surrounding macrophages (paracrine effect). Traditional methodologies have not been able to separate these serial effects. The novel methodology presented here was developed to separate autocrine and paracrine effects by using a simple mathematical model to interpret the effects of dilution on apoE-mediated cholesterol efflux. Our results show that, at very dilute concentrations, the paracrine effect of apoE is not evident and the autocrine effect becomes the dominant mediator of efflux. However, at saturating concentrations, paracrine apoE causes 80 -90% of the apoE-mediated cholesterol efflux, whereas autocrine apoE is responsible for the remaining 10 -20%. These results suggest that the relative importance of autocrine and paracrine apoE depends on the size of the local distribution volume, a factor not considered in previous in vitro studies of apoE function. Furthermore, autocrine effects of apoE could be critical in the prevention of foam cell formation in vivo. This novel methodology may be applicable to other types of mixed autocrine/paracrine systems, such as signal transduction systems. autocrine/paracrine system; cholesterol acceptor; extracellular space; distribution volume AN IMPORTANT CHALLENGE in atherosclerosis research is the characterization of the effects of locally synthesized apolipoprotein E (apoE) within the vessel wall. Endogenous synthesis and secretion of apoE by macrophages in the vessel wall have been shown to protect against atherosclerosis (22). Arterial macrophages participate in inflammation, tissue remodeling, and lipid metabolism. ApoE, which is synthesized by hepatocytes, adipocytes, and macrophages, mediates lipoprotein metabolism and affects cellular cholesterol homeostasis. apoE from macrophages accepts cholesterol from cells in the vessel wall and transports it back to the liver, where the cholesterol can be excreted as bile (3,9). This pathway is called the reverse cholesterol transport (RCT) system. The effect of apoE can be due to its cellular or extracellular positioning, and therefore an apoE molecule can mediate cholesterol efflux from the macrophage that originally secreted it (autocrine effect) or from surrounding macrophages (paracrine effect). The terms "autocrine" and "paracrine," traditionally applied to signaling peptides and hormones, have also been used to describe the actions of mediators with a broad range of functions besides signal transduction (1,7,25). It can be assumed that for the sake of cholesterol efflux an individual macrophag...

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Apolipoprotein E Inhibits Serum-stimulated Cell Proliferation and Enhances Serum-independent Cell Proliferation

Cited by 23 publications

References 34 publications

Evidence of Functional Modulation of the MEKK/JNK/cJun Signaling Cascade by the Low Density Lipoprotein Receptor-related Protein (LRP)

Evidence of Functional Modulation of the MEKK/JNK/cJun Signaling Cascade by the Low Density Lipoprotein Receptor-related Protein (LRP)

Apolipoprotein E expression promotes lung adenocarcinoma proliferation and migration and as a potential survival marker in lung cancer

ApoE-mediated cholesterol efflux from macrophages: separation of autocrine and paracrine effects

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