Identification of a novel transcription factor, ELYS, expressed predominantly in mouse foetal haematopoietic tissues

Kimura, Naoki; Takizawa, Makiko; Okita, Keisuke; Natori, Osamu; Igarashi, Katsuhide; Ueno, Masaya; Nakashima, Kin Ichi; Nobuhisa, Ikuo; Taga, Tetsuya

doi:10.1046/j.1365-2443.2002.00529.x

Cited by 39 publications

(47 citation statements)

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“…NM026375.1) was trapped. Elys is speculated to have a major role in development of extraembryonic membranes and hematopoietic cell lineages (10)(11)(12). We ruled out the human ELYS gene as a relevant astrocytoma tumor suppressor gene by demonstrating expression by RT-PCR in a panel of established human GBM specimens (data not shown).…”

Section: Resultsmentioning

confidence: 99%

GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model

Kamnasaran

Qian

Hawkins

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Malignant astrocytomas are the most common and lethal adult primary brain tumor. Retroviral gene trapping of nontransformed neonatal astrocytes from a glial fibrillary acidic protein (GFAP): V12 HaRas murine astrocytoma model led to isolation of the transcription factor Gata6. Loss of Gata6 resulted in enhanced proliferation and transformation of astrocytes. Human malignant astrocytoma cell lines, explant xenografts, and operative specimens demonstrated loss of GATA6 expression. Loss-of-function GATA6 mutations with loss of heterozygosity of the GATA6 locus were found in human malignant astrocytoma specimens but not in lower-grade astrocytomas or normal adult astrocytes. Knockdown of Gata6 expression in V12 Ha-Ras or p53؊/؊ astrocytes, but not in parental murine or human astrocytes, led to acceleration of tumorgenesis. Knockin GATA6 expression in human malignant astrocytoma cells reduced their tumorgenic growth with decreased VEGF expression. Collectively, these data demonstrate that GATA6, isolated from a murine astrocytoma model, is a novel tumor suppressor gene that is a direct target of mutations during malignant progression of murine and human astrocytomas. This work also demonstrates the utility of random mutagenesis strategies, such as gene trapping, on murine cancer models toward discovery of novel genetic alterations in corresponding human cancers.

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Section: Resultsmentioning

confidence: 99%

GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model

Kamnasaran

Qian

Hawkins

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Mutations in MEL-28, the Caenorhabditis elegans homologue of ELYS, show clear defects in nuclear envelope morphology and function, consistent with this role (Fernandez and Piano, 2006;Galy et al, 2006). Vertebrate ELYS is a large 270-kDa protein with putative nuclear localization signal (NLSs), nuclear export signals (NESs), WD repeats and an AT-hook DNA-binding motif (Kimura et al, 2002). ELYS was originally proposed to be a transcription factor involved in murine embryonic hematopoiesis (Kimura et al, 2002).…”

Section: Introductionmentioning

confidence: 86%

“…ELYS has a putative AT-hook DNA-binding motif (Kimura et al, 2002) and is indeed chromatin associated (Galy et al, 2006;Franz et al, 2007;Gillespie et al, 2007). To better understand the interaction between chromatin and ELYS, we set out to specifically mutate the ELYS AT-hook motif to test whether it actually plays a role in the chromatin binding of ELYS.…”

Section: The Elys C-terminus Contains Both At-hook and Non-at-hook Chmentioning

confidence: 99%

“…Vertebrate ELYS is a large 270-kDa protein with putative nuclear localization signal (NLSs), nuclear export signals (NESs), WD repeats and an AT-hook DNA-binding motif (Kimura et al, 2002). ELYS was originally proposed to be a transcription factor involved in murine embryonic hematopoiesis (Kimura et al, 2002). The subsequent finding that knockout mice lacking ELYS die well before hematopoiesis, however, suggested an earlier and broader role for ELYS in the cell (Okita et al, 2004).…”

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confidence: 99%

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Capture of AT-rich Chromatin by ELYS Recruits POM121 and NDC1 to Initiate Nuclear Pore Assembly

Rasala

Ramos

Harel

et al. 2008

MBoC

146

201

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Assembly of the nuclear pore, gateway to the genome, from its component subunits is a complex process. In higher eukaryotes, nuclear pore assembly begins with the binding of ELYS/MEL-28 to chromatin and recruitment of the large critical Nup107-160 pore subunit. The choreography of steps that follow is largely speculative. Here, we set out to molecularly define early steps in nuclear pore assembly, beginning with chromatin binding. Point mutation analysis indicates that pore assembly is exquisitely sensitive to the change of only two amino acids in the AT-hook motif of ELYS. The dependence on AT-rich chromatin for ELYS binding is borne out by the use of two DNA-binding antibiotics. AT-binding Distamycin A largely blocks nuclear pore assembly, whereas GC-binding Chromomycin A 3 does not. Next, we find that recruitment of vesicles containing the key integral membrane pore proteins POM121 and NDC1 to the forming nucleus is dependent on chromatin-bound ELYS/Nup107-160 complex, whereas recruitment of gp210 vesicles is not. Indeed, we reveal an interaction between the cytoplasmic domain of POM121 and the Nup107-160 complex. Our data thus suggest an order for nuclear pore assembly of 1) AT-rich chromatin sites, 2) ELYS, 3) the Nup107-160 complex, and 4) POM121-and NDC1-containing membrane vesicles and/or sheets, followed by (5) assembly of the bulk of the remaining soluble pore subunits. INTRODUCTIONThe possession of a nuclear envelope (NE) that encompasses the genome is the defining characteristic of all eukaryotes. The envelope consists of double nuclear membranes, hundreds to thousands of nuclear pore complexes (NPCs), and in higher eukaryotes, a nuclear lamina. Bidirectional transport of protein and RNA molecules through the nuclear envelope is mediated exclusively by NPCs, large structures ϳ60 -125 MDa in size (Reichelt et al., 1990;Macara, 2001;Quimby and Corbett, 2001;Goldfarb et al., 2004;Pemberton and Paschal, 2005;Patel et al., 2007).In higher eukaryotes the nuclear envelope, including pore complexes, disassembles at mitosis as a prelude to spindle assembly and chromosome segregation (Burke and Ellenberg, 2002;Margalit et al., 2005;Prunuske et al., 2006). This disassembly then necessitates nuclear envelope reformation around each set of segregated chromosomes toward the end of mitosis, a process that involves both nuclear membrane recruitment and nuclear pore formation.Analysis of the pore subunits produced by mitotic disassembly has provided the most useful clues to nearest neighbor interactions within the vertebrate pore. Vertebrate nuclear pores are comprised of ϳ30 different proteins or nucleoporins (Nups) in 8-32 copies each, to give a 500-1000 protein structure (Cronshaw et al., 2002). At mitosis the massive vertebrate pore disassembles into ϳ14 soluble subunits, each with a distinct protein composition, whereas the integral membrane pore proteins, POM121, NDC1, and gp210, segregate into endoplasmic reticulum (ER) sheets and vesicles (Gerace et al., 1982;Wozniak et al., 1989;Greber et al., 1990;Hallberg ...

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“…Mel-28/ELYS was identified in a screen in C. elegans for factors involved in pronuclear formation and in its absence the Nup107/160 complex is no longer recruited to chromatin [61,62]. Mel-28/ELYS contains an AT-hook domain [63] and the simplest model is that it binds directly to DNA and recruits the Nup107/16o complex. RanGTP stimulates Mel-28/ELYS recruitment [62], revealing yet another Ran-mediated step in NE formation [23].…”

Section: Ne Reformationmentioning

confidence: 99%

The life cycle of the metazoan nuclear envelope

Anderson

Hetzer

2008

Current Opinion in Cell Biology

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The nuclear envelope is a double-layered membrane that encloses the nuclear genome and transcriptional machinery. In dividing cells of metazoa, the nucleus completely disassembles during mitosis creating the need to re-establish the nuclear compartment at the end of each cell division. Given the crucial role of the nuclear envelope in gene regulation and cellular organization, it is not surprising that its biogenesis and organization have become active research areas. We will review recent insights into nuclear membrane dynamics during the cell cycle. IntroductionA physical membrane barrier around the nucleus was first suspected almost 100 years ago based on micromanipulation studies [1]. Later, electron microscopy (EM) images revealed that these 'nuclear envelopes' consist of two parallel membranes, the inner (INM) and outer nuclear membrane (ONM) [2]. Both membranes are penetrated by nuclear pore complexes (NPCs), large protein assemblies that mediate bidirectional exchange of molecules between the nucleoplasm and the cytoplasm [3]. The ONM is continuous with the endoplasmic reticulum (ER) and is studded with ribosomes. Although lipids can diffuse freely between the NE and the ER (Figure 1, Interphase), the protein composition of the NE differs dramatically from ER tubules and sheets. This indicates specific mechanisms of protein targeting and unique roles of the NE in regulating nuclear functions. Research of the last few years has revealed active roles of the NE in the organization of chromatin and the cytoskeleton as well as in cell cycle progression [4]. For instance, recent studies have demonstrated that heterochromatin tightly associates with the INM and the targeting of certain chromatin regions to the NE directly controls gene expression [5][6][7]. NE proteins, which mediate the multiple NE functions, can be categorized in essentially four classes: components of the nuclear pore, INM-and ONM-proteins and lamins. The first group is composed of ∼30 proteins, nucleoporins, which constitute the NPCs, the exclusive sites of nucleocytoplasmic transport [3]. NPCs form hollow cylinders with nucleoplasmic and cytoplasmic filamentous attachments that together form a transport channel across the lipid bilayer [8]. Although NPCs are membrane embedded, only three transmembrane nucleoporins have been identified, leaving us with the puzzle of how this ∼90 MDa complex assembles. A detailed model of the molecular architecture of the yeast NPC was recently proposed based on biophysical and proteomic parameters [9], and is likely to provide important insights into the pore structure in metazoa since the overall shape and protein folds seem to have been conserved throughout evolution. The second group of proteins, which specifically localizes to the INM [10], links the NE to chromatin organization. For instance, several integral membrane proteins such as emerin, lamin B receptor, Lap 2β and MAN1 have been shown to interact with regulators of chromatin organization (e.g. HP1 and BAF) and transcription factors [11,12] The ...

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Identification of a novel transcription factor, ELYS, expressed predominantly in mouse foetal haematopoietic tissues

Abstract: Background : The precise mechanism governing the generation of haematopoietic stem cells still remains to be understood, partly because the molecules required for early haematopoiesis have not fully been identified.

Cited by 39 publications

References 40 publications

GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model

GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model

Capture of AT-rich Chromatin by ELYS Recruits POM121 and NDC1 to Initiate Nuclear Pore Assembly

The life cycle of the metazoan nuclear envelope

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