Protein Kinase A-regulated Nucleocytoplasmic Shuttling of Id1 during Angiogenesis

Nishiyama, Koichi; Takaji, Kentaro; Uchijima, Yasunobu; Kurihara, Yukiko; Asano, Tomohiko; Yoshimura, Michihiro; Ogawa, Hisao; Kurihara, Hiroki

doi:10.1074/jbc.m611609200

Cited by 23 publications

(19 citation statements)

References 48 publications

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“…3), showing that the amount of Id1 is not regulated at the protein level in the context of HGF signaling. A recent report showed that Id1 protein undergoes nucleocytoplasmic shuttling (44), which is also involved in regulating its degradation (37). Our preliminary data showed that the localization of Id1 protein is not altered by HGF treatment in HepG2 cells (data not shown), also supporting that the rate of degradation of Id1 protein is not affected by HGF treatment.…”

Section: Discussionsupporting

confidence: 71%

Id1 Is Down-Regulated by Hepatocyte Growth Factor via ERK-Dependent and ERK-Independent Signaling Pathways, Leading to Increased Expression of p16INK4a in Hepatoma Cells

Ushio

Hashimoto

Kitamura

et al. 2009

Molecular Cancer Research

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Hepatocyte growth factor (HGF) inhibits the proliferation of several tumor cell lines and tumor growth in vivo. We showed previously that HGF induces cell cycle arrest at G 1 in a human hepatoma cell line, HepG2, by up-regulating the expression of p16INK4a through strong activation of extracellular signal-regulated kinase (ERK). However, although essential, the activation was not sufficient for the up-regulation of p16. In this study, we examined regulatory mechanisms of p16 expression through a transcription factor, Ets, which has been shown previously to bind to the promoter. The treatment of HepG2 cells with HGF induced ERK-dependent phosphorylation of Ets, which leads to its activation, before the up-regulation of p16, suggesting that another factor suppresses Ets activity. We found that HGF reduces the amount of Id1, which is a dominant-negative inhibitor of Ets, leading to a decrease in Ets associated with Id1. Id1 was down-regulated via transcriptional regulation not via the ubiquitin-proteasome-mediated pathway. Inhibition of the HGF-induced high-intensity ERK activity had a modest effect on the Id1 down-regulation, and inhibition of the phosphatidylinositol 3-kinase pathway had no effect, showing that Id1 is regulated by ERK-dependent and -independent pathways other than the phosphatidylinositol 3-kinase pathway. Exogenously expressed Id1 suppressed the up-regulation of p16 by HGF and the antiproliferative effect of HGF. Knockdown of Id1 significantly enhanced the activity of the p16 promoter coordinately with the activation of ERK. Our results indicated that down-regulation of Id1 plays a key role in the inhibitory effect of HGF on cell proliferation and provides a molecular basis for cancer therapy with HGF.

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Section: Discussionsupporting

confidence: 71%

Id1 Is Down-Regulated by Hepatocyte Growth Factor via ERK-Dependent and ERK-Independent Signaling Pathways, Leading to Increased Expression of p16INK4a in Hepatoma Cells

Ushio

Hashimoto

Kitamura

et al. 2009

Molecular Cancer Research

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“…ID family genes regulate cell cycle and cell fate, and they play essential roles in angiogenesis (3,24,39). Specifically, it has been demonstrated that ID1 can increase the proliferation activity of endothelial cells (45,52) and also preserve endothelial cell commitment in stem cell derived endothelial cells (31). Furthermore, Ling et.…”

Section: Discussionmentioning

confidence: 99%

“…After the preconditioned control sample was obtained, the mean shear stress was doubled. At each designated time point (5,15,45,90,180, and 360 min after step-up), one randomly selected chamber was detached from the flow circuit and immediately disassembled for RNA isolation. RNA isolation and amplification were performed as described previously (62).…”

Section: Methodsmentioning

confidence: 99%

Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude

Zhang

Friedman

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Zhang J, Friedman MH. Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude. Am J Physiol Heart Circ Physiol 302: H983-H991, 2012. First published December 2, 2011; doi:10.1152/ajpheart.00168.2011.-The adaptation of vascular endothelial cells to shear stress alteration induced by global hemodynamic changes, such as those accompanying exercise or digestion, is an essential component of normal endothelial physiology in vivo. An understanding of the transient regulation of endothelial phenotype during adaptation to changes in mural shear will advance our understanding of endothelial biology and may yield new insights into the mechanism of atherogenesis. In this study, we characterized the adaptive response of arterial endothelial cells to an acute increase in shear stress magnitude in well-defined in vitro settings. Porcine endothelial cells were preconditioned by a basal level shear stress of 15 Ϯ 15 dyn/cm 2 at 1 Hz for 24 h, after which an acute increase in shear stress to 30 Ϯ 15 dyn/cm 2 was applied. Endothelial permeability nearly doubled after 40-min exposure to the elevated shear stress and then decreased gradually. Transcriptomics studies using microarray techniques identified 86 genes that were sensitive to the elevated shear. The acute increase in shear stress promoted the expression of a group of anti-inflammatory and antioxidative genes. The adaptive response of the global gene expression profile is triphasic, consisting of an induction period, an early adaptive response (ca. 45 min) and a late remodeling response. Our results suggest that endothelial cells exhibit a specific phenotype during the adaptive response to changes in shear stress; this phenotype is different than that of fully adapted endothelial cells. permeability; gene expression; microarray ATHEROSCLEROSIS ARISES FROM endothelial cell dysfunction. Endothelial dysfunction features increased permeability, enhanced expression of adhesion molecules and leukocyte adhesion, enhanced cell turnover, increased oxidant stress, and reduced endothelium-dependent vasodilation (51). Increased endothelial permeability leads to the accumulation of LDL in the intima, which is a key step in atherosclerotic development. The inflammatory response of endothelial cells results in the recruitment of monocytes, which migrate into the intima and differentiate into macrophages, which engulf oxidized LDL and form foam cells. The accumulation of foam cells in the intima leads to the formation of atherosclerotic plaques. Therefore, endothelial permeability and inflammatory status greatly affect arterial atherosusceptibility.Endothelial cells in the vasculature are constantly exposed to shear stress. Shear-dependent permeability to macromolecules has been examined both in vitro and in vivo. The application of shear stress to static cultured cells increased endothelial permeability to albumin (32) and dextran (50). However, these increases may have been caused by the transient response of endothelial cells to the onset of shear...

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“…Cells were treated with methanol vehicle or the nuclear export inhibitor leptomycin B (LMB, 10 nM). This concentration of LMB has been shown to block nucleocytoplasmic shuttling of Id1 in other cells (28). In the vehicle-treated cells, co-expression of RFP-AF17 with GFP-Dot1a reduced the levels of H3 me2K79 and H3 me3K79 to about 40 and 30% that of the control level (compare lane 2 with lane 1 in the corresponding blots, Fig.…”

Section: Af17 Decreases H3 K79 Methylation In Bulk Histones Possiblymentioning

confidence: 99%

AF17 Competes with AF9 for Binding to Dot1a to Up-regulate Transcription of Epithelial Na+ Channel α

Reisenauer

Anderson

Huang

et al. 2009

Journal of Biological Chemistry

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We previously reported that Dot1a⅐AF9 complex represses transcription of the epithelial Na ؉ channel subunit ␣ (␣-ENaC) gene in mouse inner medullary collecting duct mIMCD3 cells and mouse kidney. Aldosterone relieves this repression by down-regulating the complex through various mechanisms. Whether these mechanisms are sufficient and conserved in human cells or can be applied to other aldosteroneregulated genes remains largely unknown. Here we demonstrate that human embryonic kidney 293T cells express the three ENaC subunits and all of the ENaC transcriptional regulators examined. These cells respond to aldosterone and display benzamil-sensitive Na ؉ currents, as measured by whole-cell patch clamping. We also show that AF17 and AF9 competitively bind to the same domain of Dot1a in multiple assays and have antagonistic effects on expression of an ␣-ENaC promoter-luciferase construct. Overexpression of Dot1a or AF9 decreased mRNA expression of the ENaC subunits and their transcriptional regulators and reduced benzamil-sensitive Na ؉ currents. AF17 overexpression caused the opposite effects, accompanied by redirection of Dot1a from the nucleus to the cytoplasm and reduction in histone H3 K79 methylation. The nuclear export inhibitor leptomycin B blocked the effect of AF17 overexpression on H3 K79 hypomethylation. RNAi-mediated knockdown of AF17 yielded nuclear enrichment of Dot1a and histone H3 K79 hypermethylation. As with AF9, AF17 displays nuclear and cytoplasmic co-localization with Sgk1. Therefore, AF17 competes with AF9 to bind Dot1a, decreases Dot1a nuclear expression by possibly facilitating its nuclear export, and relieves Dot1a⅐AF9-mediated repression of ␣-ENaC and other target genes.Failure of Na ϩ homeostasis contributes to hypertension, cardiovascular disease, and respiratory diseases such as cystic fibrosis (1). The importance of the epithelial Na ϩ channel (ENaC) 3 in the regulation of salt homeostasis and blood pressure is demonstrated by the association of gain-and loss-offunction mutations in its subunits with genetic hypertensive and hypotensive diseases, such as Liddle syndrome (2) and pseudohypoaldosteronism type 1 (3). ENaC consists of three partially homologous subunits (␣, ␤, and ␥), and their expression on the cell surface constitutes the rate-limiting step in active Na ϩ and fluid absorption in the apical membrane of saltabsorbing epithelia. Aldosterone treatment or hyperaldosteronism caused by Na ϩ limitation induces ␣-ENaC transcription in the aldosterone-sensitive distal nephron. In these cells synthesis of ␣-ENaC is believed to be the rate-limiting step in Na ϩ channel formation. As a major regulator of epithelial Na ϩ absorption, aldosterone imposes a tight and complex regulation of ENaC at multiple levels including transcription, trafficking to the cell membrane, and degradation and acts at least partially through ␣-ENaC induction in the renal collecting duct (4, 5).We recently identified and characterized a new aldosterone signaling network involving the murine disruptor of telomer...

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Protein Kinase A-regulated Nucleocytoplasmic Shuttling of Id1 during Angiogenesis

Cited by 23 publications

References 48 publications

Id1 Is Down-Regulated by Hepatocyte Growth Factor via ERK-Dependent and ERK-Independent Signaling Pathways, Leading to Increased Expression of p16INK4a in Hepatoma Cells

Id1 Is Down-Regulated by Hepatocyte Growth Factor via ERK-Dependent and ERK-Independent Signaling Pathways, Leading to Increased Expression of p16INK4a in Hepatoma Cells

Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude

AF17 Competes with AF9 for Binding to Dot1a to Up-regulate Transcription of Epithelial Na+ Channel α

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