Jade-1, a candidate renal tumor suppressor that promotes apoptosis

Zhou, Mina I.; Foy, Rebecca L.; Chitalia, Vipul C.; Zhao, Jimin; Panchenko, Mikhail P.; Wang, Hongmei; Cohen, Herbert T.

doi:10.1073/pnas.0500757102

Cited by 66 publications

(76 citation statements)

References 17 publications

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“…Recently, ING4 protein was found associated to the HAT complex containing HBO1, hEafS and JADE1/2/3 proteins (Zhou et al, 2005;Doyon et al, 2006;Russell et al, 2006). Different mutations in the ING4 transcript were detected in several cancer cell lines, and for all of them a loss of function effect has been proposed.…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…Like Tip60, HBO1's interaction with the AR (Sharma et al, 2000) putatively connects it to development of prostate cancer, whereas its functional link with NF-kB (Contzler et al, 2006) may lead to tumour suppression. The interaction between the HBO1 complex subunit Jade-1 and the von Hippel-Lindau tumour suppressor correlates with protection from renal cancer (Zhou et al, 2005), suggesting that HBO1 function may be connected to that malignancy and to the von Hippel-Lindau disease. The presence of HBO1 in complexes with the tumour suppressors ING4 and -5 (Doyon et al, 2006) further implies that it may play a role in protection from malignancy.…”

Section: Hbo1 and Cancermentioning

confidence: 99%

The MYST family of histone acetyltransferases and their intimate links to cancer

2007

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The histone acetyltransferases (HATs) of the MYST family are highly conserved in eukaryotes and carry out a significant proportion of all nuclear acetylation. These enzymes function exclusively in multisubunit protein complexes whose composition is also evolutionarily conserved. MYST HATs are involved in a number of key nuclear processes and play critical roles in genespecific transcription regulation, DNA damage response and repair, as well as DNA replication. This suggests that anomalous activity of these HATs or their associated complexes can easily lead to severe cellular malfunction, resulting in cell death or uncontrolled growth and malignancy. Indeed, the MYST family HATs have been implicated in several forms of human cancer. This review summarizes the current understanding of these enzymes and their normal function, as well as their established and putative links to oncogenesis.

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“…JADE1, a candidate tumor suppressor, has been physically linked to von Hippel-Lindau (VHL) function, transcription regulation, Wnt signaling, and apoptosis (6,40,(74)(75)(76). Our initial purification of HBO1 acetyltransferase complexes identified full-length JADE1/2/3 paralogues as stably associated subunits (8).…”

Section: Myst-ing Hat Complexes Can Be Separated Into Three Classesmentioning

confidence: 99%

“…2A) (12,53). In fact, the bulk of functional information on JADE1 in the literature is based on this smaller 509-amino-acid protein produced by an abundant mRNA splice variant (40,(74)(75)(76).…”

Section: Myst-ing Hat Complexes Can Be Separated Into Three Classesmentioning

confidence: 99%

Conserved Molecular Interactions within the HBO1 Acetyltransferase Complexes Regulate Cell Proliferation

Avvakumov

Lalonde

Saksouk

et al. 2012

Molecular and Cellular Biology

128

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Acetyltransferase complexes of the MYST family with distinct substrate specificities and functions maintain a conserved association with different ING tumor suppressor proteins. ING complexes containing the HBO1 acetylase are a major source of histone H3 and H4 acetylation in vivo and play critical roles in gene regulation and DNA replication. Here, our molecular dissection of HBO1/ING complexes unravels the protein domains required for their assembly and function. Multiple PHD finger domains present in different subunits bind the histone H3 N-terminal tail with a distinct specificity toward lysine 4 methylation status. We show that natively regulated association of the ING4/5 PHD domain with HBO1-JADE determines the growth inhibitory function of the complex, linked to its tumor suppressor activity. Functional genomic analyses indicate that the p53 pathway is a main target of the complex, at least in part through direct transcription regulation at the initiation site of p21/CDKN1A. These results demonstrate the importance of ING association with MYST acetyltransferases in controlling cell proliferation, a regulated link that accounts for the reported tumor suppressor activities of these complexes. Members of the ING (inhibitor of growth) family of growth regulators are present in all eukaryotes, with the five human proteins (ING1 to ING5) and the three from Saccharomyces cerevisiae (Yng1, Yng2, and Pho23) being the most studied. Their homology is highest at the carboxyl termini within a plant homeodomain (PHD) finger-a motif common to many chromatin regulatory proteins (8, 54). Expression analyses of several tumor types show that ING genes are either mutated or downregulated in many forms of cancer (43,73), and a number of studies have implicated the ING proteins in the regulation of the cell cycle and proliferation, cellular aging and senescence, hormone signaling pathways, brain tumor growth, and angiogenesis (reviewed in reference 51). These functions stem from direct mechanistic roles in chromatin modification and remodeling, gene-specific transcription regulation, and DNA repair, recombination, and replication (2, 54, 61).The multisubunit protein complexes containing ING family members have been purified and characterized from yeast and human cells (reviewed in references 2 and 54). The human INGs can be divided into three groups-ING1/2, ING3, and ING4/5-based on their association with three distinct types of protein complexes (8). Each of these complexes regulates chromatin modification and structure via histone acetylation and deacetylation. The ING complexes that carry out histone acetylation contain members of the MYST family of histone acetyltransferases (HATs) as their catalytic subunits (Fig. 1A). Human MYST HATs include Tip60 (KAT5), HBO1 (KAT7), MOZ (KAT6A), MORF (KAT6B), and MOF (KAT8). These enzymes are also known to play crucial roles in transcription activation and in DNA repair, recombination, and replication and are implicated in development and many human diseases, most notably cancer (2,14,...

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Jade-1, a candidate renal tumor suppressor that promotes apoptosis

Cited by 66 publications

References 17 publications

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

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

The MYST family of histone acetyltransferases and their intimate links to cancer

Conserved Molecular Interactions within the HBO1 Acetyltransferase Complexes Regulate Cell Proliferation

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