Beadex encodes an LMO protein that regulates Apterous LIM–homeodomain activity in Drosophila wing development: a model for LMO oncogene function

Milán, Marco; Díaz-Benjumea, Fernando J.; Cohen, Stephen M.

doi:10.1101/gad.12.18.2912

Cited by 144 publications

(178 citation statements)

References 54 publications

(50 reference statements)

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“…All three genes were altered in the same direction in both cell lines, suggesting that in MCF-7 cells, LMO4 upregulation functions by disrupting Clim-containing transcription A2 A3 A4 A5 A6 B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15 B16 L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12 L13 L14 L15 L16 L17 L18 L19 L20 L21 L22 L23 L24 L25 L26 LMO4 and regulation of BMP7 gene expression N Wang et al complexes on these responsive genes. This is similar to the Drosophila wing where LMO4 upregulation and DN-Clim have similar effects (Milan et al, 1998). We used quantitative real-time PCR to validate the microarray results for several LMO4-responsive genes, including BMP7 (Figure 3b).…”

Section: Identification Of Lmo4-responsive Genesmentioning

confidence: 60%

“…LMOs are proposed to function as transcriptional activators by recruiting Clims to DNA-binding proteins. LMOs can also feedback inhibit LIM homeodomain function by displacing Clim from LIM homeodomain proteins (Milan et al, 1998). Recently, chromatin-modifying transcriptional cofactors, including HDACs have been identified as LMO4 interactors (Singh et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

Wang

Lin

et al. 2007

Oncogene

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The nuclear LIM-only protein 4 (LMO4) is upregulated in breast cancer, especially estrogen receptor-negative tumors, and its overexpression in mice leads to hyperplasia and tumor formation. Here, we show that deletion of LMO4 in the mammary glands of mice leads to impaired lobuloalveolar development due to decreased epithelial cell proliferation. With the goal of discovering potential LMO4-target genes, we also developed a conditional expression system in MCF-7 cells for both LMO4 and a dominant negative (DN) form of its co-regulator, cofactor of LIM domains (Clim/Ldb/Nli). We then used DNA microarrays to identify genes responsive to LMO4 and DN-Clim upregulation. One of the genes common to both data sets was bone morphogenic protein 7 (BMP7), whose expression is also significantly correlated with LMO4 transcript levels in a large dataset of human breast cancers, suggesting that BMP7 is a bona fide target gene of LMO4 in breast cancer. Inhibition of BMP7 partially blocks the effects of LMO4 on apoptosis, indicating that BMP7 mediates at least some functions of LMO4. Gene transfer studies show that LMO4 regulates the BMP7 promoter, and chromatin immunoprecipitation studies show that LMO4 and its cofactor Clim2 are recruited to the BMP7 promoter. Furthermore, we demonstrate that HDAC2 recruitment to the BMP7 promoter is inhibited by upregulation of LMO4 and that HDAC2 knockdown upregulates the promoter. These studies suggest a novel mechanism of action for LMO4: LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and increased LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.

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Section: Identification Of Lmo4-responsive Genesmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

Wang

Lin

et al. 2007

Oncogene

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“…The LIM domain of LDBs contributes to the binding of transcription factors, including LIM-homeodomain, zinc-finger and basic helixloop -helix (bHLH) proteins (Agulnick et al, 1996;Jurata et al, 1996;Bach et al, 1997;Morcillo et al, 1997). Formation of protein complexes synergistically activates the expression of target genes Milán et al, 1998). In the presence of LMO protein, it mediates the transcription factor binding to the LDB protein or competes with the direct binding between LDB and the transcription factor (Rabbitts, 1998;Thaler et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…LDB proteins bind to transcription factors directly or indirectly mediated through LMO proteins, and then bridge a unique bipartite DNA sequence separated by about one helix turn from each other (Agulnick et al, 1996;Jurata et al, 1996;Wadman et al, 1997;Rabbitts, 1998). Both LMOs and LDBs are widely expressed during development (Kenny et al, 1998;Millan et al, 1998;Toyama et al, 1998;Hermanson et al, 1999) and appear to have essential functions in cell proliferation and lineage determination, and oncogenesis Milán et al, 1998;Rabbitts, 1998;Thaler et al, 2002).…”

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confidence: 99%

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

et al. 2003

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Carcinoma cells can lose their epithelial cell characteristics and dedifferentiate into a fibroblast-like cell during progression of a neoplasm. Aberrant expression of oligomeric transcriptional complexes contributes to progression of carcinomas. Although individual transcription factors initiating progression remain unknown, LIM-only protein (LMO) and LIM-domain binding protein (LDB) negatively regulate breast carcinoma cell differentiation. In this study, we investigated the expression of LMO4 and LDB in squamous cell carcinomas of the oral cavity. LMO4 mRNA was amplified in four of six carcinoma tissues and eight of 12 carcinoma cell lines, and LDB1 in three carcinoma tissues and 11 cell lines examined. Immunoprecipitation studies revealed that LMO4 and LDB1 interact with each other in the nuclear milieu of the carcinoma cells indicating the presence of an LMO4-LDB1-mediated transcription complex. Both LMO4 and LDB1 proteins were preferentially localised in the nuclei of carcinoma cells at the invasive front and the immunoreactivity was increased in less-differentiated carcinoma tissues (Po0.01). Carcinoma cells metastasised to the cervical lymph nodes with increased immunoreactivity compared to the primary site of neoplasm (Po0.05). These data suggest that the LMO4 -LDB1 complexes may be involved in carcinoma progression possibly through dedifferentiation of squamous carcinoma cells of the oral cavity.

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“…Some (though not all) zip 2 / zip Ebr animals can survive to early pupal stages. The influence of zip on D-V compartmentalization in these animals was then assessed by staining for a marker of dorsal cell fate, Beadex (Bx, also known as dLMO) (Milan et al, 1998).…”

Section: A Distinct Requirement For Myosin II At the D-v Compartment mentioning

confidence: 99%

Localization and requirement for Myosin II at the dorsal‐ventral compartment boundary of the Drosophila wing

Major

Irvine

2006

Developmental Dynamics

124

134

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As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries. Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton. Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization. These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization. Developmental Dynamics 235: 3051-3058, 2006.

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Beadex encodes an LMO protein that regulates Apterous LIM–homeodomain activity in Drosophila wing development: a model for LMO oncogene function

Cited by 144 publications

References 54 publications

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

Localization and requirement for Myosin II at the dorsal‐ventral compartment boundary of the Drosophila wing

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