The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF)

Ozer, Abdullah; Wu, Leeju C.; Bruick, Richard K.

doi:10.1073/pnas.0502716102

Cited by 150 publications

(151 citation statements)

References 34 publications

(38 reference statements)

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“…Interestingly, it has been shown that tumors lacking ING4 showed increased vascularization compared with ING4 expressing tumors [118]. Moreover, ING4 down-regulated angiogenesis related molecules including IL-8 and HIF-1α [117,119]. In line with these observations it has been shown that ING4 nuclear level is reduced in myeloma cells as compared to normal plasma cells, and that ING4 regulates IL-8 and OPN production by myeloma cells both in normoxia and hypoxia [95].…”

Section: Genes Involved In the Regulation Of The Pro-angiogenic Profimentioning

confidence: 75%

Angiogenesis and Multiple Myeloma

Giuliani

Storti

Bolzoni

et al. 2011

Cancer Microenvironment

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The bone marrow microenvironment in multiple myeloma is characterized by an increased microvessel density. The production of pro-angiogenic molecules is increased and the production of angiogenic inhibitors is suppressed, leading to an "angiogenic switch". Here we present an overview of the role of angiogenesis in multiple myeloma, the pro-angiogenic factors produced by myeloma cells and the microenvironment, and the mechanisms involved in the myeloma-induced angiogenic switch. Current data suggest that the increased bone marrow angiogenesis in multiple myeloma is due to the aberrant expression of angiogenic factors by myeloma cells, the subsequent increase in pro-angiogenic activity of normal plasma cells as a result of myeloma cell angiogenic activity, and the increased number of plasma cells overall. Hypoxia also contributes to the angiogenic properties of the myeloma marrow microenvironment. The transcription factor hypoxia-inducible factor-1α is overexpressed by myeloma cells and affects their transcriptional and angiogenic profiles. In addition, potential roles of the tumor suppressor gene inhibitor of growth family member 4 and homeobox B7 have also been recently highlighted as repressors of angiogenesis and pro-angiogenic related genes, respectively. This complex pathogenetic model of myeloma-induced angiogenesis suggests that several proangiogenic molecules and related genes in myeloma cells and the microenvironment are potential therapeutic targets.

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Section: Genes Involved In the Regulation Of The Pro-angiogenic Profimentioning

confidence: 75%

Angiogenesis and Multiple Myeloma

Giuliani

Storti

Bolzoni

et al. 2011

Cancer Microenvironment

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“…It is well known that ING4 is a tumor suppressor for it intervenes the activity of hypoxia inducible factor (HIF) which has an important positive role in angiogenesis and tumorigenesis. HIF promote tumor angiogenesis by inducing VEGF and other factors (Ozer et al, 2005;Colla et al, 2007). Thus, the up-regulation of VEGF by miR-150 may be mediated by ING4 (Brahimi-Horn and Pouyssegur, 2006).…”

Section: Discussionmentioning

confidence: 99%

Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF, and the neutralization of miR-150 attenuate tumor development

et al. 2013

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“…The NLS1 domain is responsible for ING4 nuclear localization and interaction with p53 Zhang et al, 2005). The PHD domain, a zinc finger motif present in many nuclear proteins (Bienz, 2006), is involved in interaction with HPH-2 (Ozer et al, 2005) and H3K4me2/3 (Pena et al, 2006;Shi et al, 2006), thus linking ING4 to regulation of gene expression. A deletion mutant lacking the C-terminal 40 amino acids, including the PHD domain, is unable to interact with p65, thus abrogating the inhibitory effect of ING4 on NF-kB activity (Garkavtsev et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Our data are in keeping with previous study showing that the deletion of the last 40 amino acids abrogates the effect of ING4 on NF-kB activa tion. Interestingly, the region lacking in ING4-DEx6A contains the PHD domain, involved in the binding to HPH-2, and H3K4me2/3 (Ozer et al, 2005;Pena et al, 2006;Shi et al, 2006). Thus, alternative splicing producing ING4-DEx6 variants could impair some important functions of ING4 and modulate its contribution to specific pathways.…”

Section: Discussionmentioning

confidence: 99%

“…ING4 mRNA resulted downregulated in gliomas and its expression decreased from lower to higher level of malignancy (Garkavtsev et al, 2004). More recently, ING4 has been shown to interact with HIF-associated prolyl hydroxylase (HPH)-2, and to regulate the activity of the hypoxia-inducible factor (HIF)-1a transcription factor, thus suppressing the expression of HIF-1a responsive genes under hypoxic conditions (Ozer et al, 2005). The interaction with HPH-2 requires the ING4 PHD domain; interestingly, such domain has been recently shown involved in the association with histone H3K4me2/3 (Pena et al, 2006;Shi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Detection of novel mRNA splice variants of human ING4 tumor suppressor gene

et al. 2007

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Inhibitor of growth (ING)4, member of a gene family encoding potential tumor suppressors, is implicated as a repressor of angiogenesis and tumor growth and suppresses loss of contact inhibition in vitro. Here, we report that ING4 undergoes alternative splicing. Expression analysis identified novel ING4 spliced variant mRNAs encoding proteins devoid of different portions. The ING4 variants were detected in both normal and tumor tissues. The existence of ING4 variants was confirmed by several approaches, including reverse transcriptase-polymerase chain reaction, real-time PCR and in silico experiments. To investigate the functional consequences of alternative splicing the ING4 variant cDNAs were expressed in mammalian cells. Our studies indicated that (i) the ING4 variants do not differ from wild-type in their nuclear localization, interaction with p53 and association to HBO1 complex; and (ii) the ING4-DEx6A variant, devoid of the C-terminal portion, loses the capability to inhibit NF-jB. On the whole our data suggest that alternative splicing could modulate the activity of ING4 tumor suppressor protein.

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The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF)

Abstract: prolyl hydroxylase ͉ inhibitor of growth

Cited by 150 publications

References 34 publications

Angiogenesis and Multiple Myeloma

Angiogenesis and Multiple Myeloma

Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF, and the neutralization of miR-150 attenuate tumor development

Detection of novel mRNA splice variants of human ING4 tumor suppressor gene

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