Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation

Zhang, Xin; Lin, Dao‐Hong; Jin, Yan; Wang, Kesheng; Zhang, Yan; Babilonia, Elisa; Wang, Zhijian; Wang, Zhiqin; Giebisch, Gerhard; Han, Ze‐Guang; Wang, Wenhui

doi:10.1073/pnas.0703383104

Cited by 8 publications

(8 citation statements)

References 35 publications

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“…This research group suggests that MAPK-induced inhibition of ROMK activity plays a predominant role in suppressing K + secretion in the early stage (<24 h) of K + depletion. Further study supports the hypothesis that ING4 (inhibitor of growth 4), which is stimulated by low K + intake dependent on superoxide anion production, may mediate the effect of a low-K + diet on MAPK to depress ROMK channel activity (67). In summary, a low-K + diet increases superoxide anion production, which, in parallel, increases the expression and activity of ( a ) PTK and ( b ) ING4 and MAPK, which in turn independently depress CCD K + channel activity and K + secretion (67).…”

Section: Molecular Mechanisms Of Renal K+ Adaptationsupporting

confidence: 68%

Recent Advances in Understanding Integrative Control of Potassium Homeostasis

Youn

McDonough

2009

Annu. Rev. Physiol.

116

108

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The potassium homeostatic system is very tightly regulated. Recent studies have shed light on the sensing and molecular mechanisms responsible for this tight control. In addition to classic feedback regulation mediated by a rise in extracellular fluid (ECF) [K+], there is evidence for a feedforward mechanism: Dietary K+ intake is sensed in the gut, and an unidentified gut factor is activated to stimulate renal K+ excretion. This pathway may explain renal and extrarenal responses to altered K+ intake that occur independently of changes in ECF [K+]. Mechanisms for conserving ECF K+ during fasting or K+ deprivation have been described: Kidney NADPH oxidase activation initiates a cascade that provokes the retraction of K+ channels from the cell membrane, and muscle becomes resistant to insulin stimulation of cellular K+ uptake. How these mechanisms are triggered by K+ deprivation remains unclear. Cellular AMP kinase–dependent protein kinase activity provokes the acute transfer of K+ from the ECF to the ICF, which may be important in exercise or ischemia. These recent advances may shed light on the beneficial effects of a high-K+ diet for the cardiovascular system.

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Section: Molecular Mechanisms Of Renal K+ Adaptationsupporting

confidence: 68%

Recent Advances in Understanding Integrative Control of Potassium Homeostasis

Youn

McDonough

2009

Annu. Rev. Physiol.

116

108

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“…The present study has further suggested that PP2B may also be involved in mediating the effect of superoxide anions on ERK and p38 phosphorylation: 1) treatment of M-1 cells or 293T cells with GO decreased the expression of PP2B-cat, and 2) inhibition of PP2B significantly stimulated the phosphorylation of p38 and ERK. The idea that the effect of K restriction on PP2B-cat is mediated by superoxide anions is also supported by the observation that K restriction did not decrease the level of PP2B-cat in gp91 phox (Ϫ/Ϫ) mice, which have been shown to produce less superoxide anion in the kidney than WT mice (46). However, further experiments are required to explore the relationship between PP2B and ING4 in mediating the effect of low K intake or superoxide anions on MAPK.…”

Section: Discussionsupporting

confidence: 50%

“…A previous study provided evidence supporting the idea that the tumor-suppressing protein inhibitor of growth 4 (ING4) is involved in mediating the effect of superoxide on MAPK in the kidney (46). First, low K intake increased ING4 expression, and suppression of superoxide abolished the effect of K restriction on ING4 expression.…”

Section: Discussionmentioning

confidence: 73%

K restriction inhibits protein phosphatase 2B (PP2B) and suppression of PP2B decreases ROMK channel activity in the CCD

Zhang

Lin²,

Wang³

et al. 2008

American Journal of Physiology-Cell Physiology

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We used Western blot analysis to examine the effect of dietary K intake on the expression of serine/ threonine protein phosphatase in the kidney. K restriction significantly decreased the expression of catalytic subunit of protein phosphatase (PP)2B but increased the expression of PP2B regulatory subunit in both rat and mouse kidney. However, K depletion did not affect the expression of PP1 and PP2A. Treatment of M-1 cells, mouse cortical collecting duct (CCD) cells, or 293T cells with glucose oxidase (GO), which generates superoxide anions through glucose metabolism, mimicked the effect of K restriction on PP2B expression and significantly decreased expression of PP2B catalytic subunits. However, GO treatment increased expression of regulatory subunit of PP2B and had no effect on expression of PP1, PP2A, and protein tyrosine phosphatase 1D. Moreover, deletion of gp91-containing NADPH oxidase abolished the effect of K depletion on PP2B. Thus superoxide anions or related products may mediate the inhibitory effect of K restriction on the expression of PP2B catalytic subunit. We also used patch-clamp technique to study the effect of inhibiting PP2B on renal outer medullary K (ROMK) channels in the CCD. Application of cyclosporin A or FK506, inhibitors of PP2B, significantly decreased ROMK channels, and the effect of PP2B inhibitors was abolished by blocking p38 mitogen-activated protein kinase (MAPK) and ERK. Furthermore, Western blot demonstrated that inhibition of PP2B with cyclosporin A or small interfering RNA increased the phosphorylation of ERK and p38 MAPK. We conclude that K restriction suppresses the expression of PP2B catalytic subunits and that inhibition of PP2B decreases ROMK channel activity through stimulation of MAPK in the CCD. potassium depletion; p38 mitogen-activated protein kinase; extracellular signal-regulated kinase 1/2; potassium secretion THE KIDNEY PLAYS A KEY ROLE in maintaining plasma K level in a normal range by secretion of K to match the dietary intake (16). Renal K secretion mainly takes place in the late distal tubule, the connecting tubule, and the cortical collecting duct (CCD) by a two-step mechanism (16, 35): K enters the cell through Na-K-ATPase at the basolateral membrane and leaves the cell through apical K channels. Although a Ca 2ϩ -activated big-conductance K (BK) channel has been shown to be involved in K secretion during high K intake or increasing tubule flow rate (6,36,43), renal outer medullary K (ROMK)-like small-conductance K (SK) channels play a major role in K secretion under normal K intake.Dietary K intake is an important factor regulating renal K secretion (13,19,33): increasing dietary K intake stimulates whereas decreasing K intake suppresses renal K secretion. However, the signaling pathway by which low K intake suppresses renal K secretion is not completely understood. We (3, 4) and others (24) have demonstrated that protein tyrosine kinases (PTK) and serine/threonine protein kinases are involved in mediating the effect of K restriction on SK channels. In ...

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“…One of the key functions of the kidney is maintaining plasma K homeostasis [167]. In renal K secretion regulation, low K intake increases ING4 expression in a superoxide-dependent manner, subsequently stimulating mitogen-activated protein kinase (MAPK) to depress renal outer medullary potassium (ROMK) channel activity [168]. Furthermore, ING4 was found to play an active role in the multi-system autoimmune disease.…”

Section: Impact On Human Disorders Other Than Cancermentioning

confidence: 99%

The essential role of tumor suppressor gene ING4 in various human cancers and non-neoplastic disorders

Cheng

2019

Bioscience Reports

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Inhibitor of growth 4 (ING4), a member of the ING family discovered in 2003, has been shown to act as a tumor suppressor and is frequently down-regulated in various human cancers. Numerous published in vivo and in vitro studies have shown that ING4 is responsible for important cancer hallmarks such as pathologic cell cycle arrest, apoptosis, autophagy, contact inhibition, and hypoxic adaptation, and also affects tumor angiogenesis, invasion, and metastasis. These characteristics are typically associated with regulation through chromatin acetylation by binding histone H3 trimethylated at lysine 4 (H3K4me3) and through transcriptional activity of transcription factor P53 and NF-κB. In addition, emerging evidence has indicated that abnormalities in ING4 expression and function play key roles in non-neoplastic disorders. Here, we provide an overview of ING4-modulated chromosome remodeling and transcriptional function, as well as the functional consequences of different genetic variants. We also present the current understanding concerning the role of ING4 in the development of neoplastic and non-neoplastic diseases. These studies offer inspiration for pursuing novel therapeutics for various cancers.

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Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation

Cited by 8 publications

References 35 publications

Recent Advances in Understanding Integrative Control of Potassium Homeostasis

Recent Advances in Understanding Integrative Control of Potassium Homeostasis

K restriction inhibits protein phosphatase 2B (PP2B) and suppression of PP2B decreases ROMK channel activity in the CCD

The essential role of tumor suppressor gene ING4 in various human cancers and non-neoplastic disorders

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