Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Plageman, Timothy F.; Yutzey, Katherine E.

doi:10.1002/dvdy.20923

Cited by 32 publications

(21 citation statements)

References 88 publications

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“…Moreover, in a recent study, a gain of Tbx5 function in cultured cardiogenic cells revealed that an equivalent human mutant (R297er) alters the ability of Tbx5a to induce some but not all target genes (35). Finally, our results point to new sequences within the Tbx5 locus in which mutations may be associated with Holt-Oram syndrome or other congenital cardiac and/or limb defects.…”

Section: Discussionsupporting

confidence: 53%

“…6E). 35 S-labeled full-length GATA-4 (G4) (E) or wild-type (WT) and mutant Nkx2.5 proteins (F). Note how Tbx5b has a greatly reduced affinity for GATA-4, and note its inability to interact with Nkx2.5.…”

Section: Resultsmentioning

confidence: 99%

“…In vitro protein-protein interactions were carried out using MBP fusion proteins for the long and short isoforms and in vitro-translated 35 S-labeled proteins in rabbit reticulocyte lysates using the T7 RNA polymerase of the TNT system (Promega Corp., Madison, WI). Binding reactions and visualization were carried out as described previously by Durocher et al (9).…”

Section: Methodsmentioning

confidence: 99%

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Distinct Expression and Function of Alternatively Spliced Tbx5 Isoforms in Cell Growth and Differentiation

Georges

Nemer

Morin

et al. 2008

Molecular and Cellular Biology

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Mutations in the T-box transcription factor Tbx5 cause Holt-Oram syndrome, an autosomal dominant disease characterized by a wide spectrum of cardiac and upper limb defects with variable expressivity. Tbx5 haploinsufficiency has been suggested to be the underlying mechanism, and experimental models are consistent with a dosage-sensitive requirement for Tbx5 in heart development. Here, we report that Tbx5 levels are regulated through alternative splicing that generates, in addition to the known 518-amino-acid protein, a C-terminal truncated isoform. This shorter isoform retains the capacity to bind DNA, but its interaction with Tbx5 collaborators such as GATA-4 is altered. In vivo, the two spliced isoforms are oppositely regulated in a temporal and growth factor-dependent manner and are present in distinct DNA-binding complexes. The expression of the long isoform correlates with growth stimulation, and its reexpression in postnatal transgenic mouse hearts promotes hypertrophy. Conversely, the upregulation of the short but not the long isoform in C2C12 myoblasts leads to growth arrest and cell death. The results provide novel insight into posttranscriptional Tbx5 regulation and point to an important role not only in cell differentiation but also in cell proliferation and organ growth. The data may help analyze genotype-phenotype relations in patients with Holt-Oram syndrome.

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Section: Discussionsupporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Distinct Expression and Function of Alternatively Spliced Tbx5 Isoforms in Cell Growth and Differentiation

Georges

Nemer

Morin

et al. 2008

Molecular and Cellular Biology

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“…One microliter of synthesized cDNA was used for analysis by qRT-PCR (MJ Research Opticon 2). Gene expression levels determined by qRT-PCR were calculated as previously reported (24,37,45,46). A standard curve was generated for each experimental primer set with either E17.5 limbs or E13.5 whole embryo cDNA, and all the values were normalized to ribosomal protein L7 expression (17).…”

Section: Methodsmentioning

confidence: 99%

Shared gene expression profiles in developing heart valves and osteoblast progenitor cells

Chakraborty

Cheek

Sakthivel

et al. 2008

Physiological Genomics

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The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, which later mature into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in developing AV valves and in bone progenitor cells. To define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV endocardial cushions compared with E17.5 AV valves (mitral and tricuspid) and with preosteoblast MC3T3-E1 (subclone4) cells. Overall, MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve maturation involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1, are predominant in E12.5 cushion. Valve maturation is characterized by differential regulation of matrix metalloproteinases and their inhibitors as well as complex collagen gene expression. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the developing valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease.

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“…T-box genes encode transcription factors involved in the regulation of developmental processes, cell-cell signaling, negative regulation of cardiac muscle cell proliferation, induction of apoptosis and negative regulation of cell migration (He et al, 2002;Mori et al, 2006;Plageman and Yutzey, 2006;Maitra et al, 2009). This gene is located on human chromosome 12q24.1.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer

Cheung

et al. 2010

Oncogene

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T-box transcription factor 5 (TBX5) is a member of a phylogenetically conserved family of genes involved in the regulation of developmental processes. The function of TBX5 in cancer development is largely unclear. We identified that TBX5 was preferentially methylated in cancer using methylation-sensitive arbitrarily primed PCR. We aim to clarify the epigenetic inactivation, biological function and clinical significance of TBX5 in colon cancer. Promoter methylation was evaluated by combined bisulfite restriction analysis and bisulfite genomic sequencing. Cell proliferation was examined by cell viability assay and colony formation assay, apoptosis by flow cytometry and cell migration by wound-healing assay. TBX5 target genes were identified by cDNA microarray analysis. Cox regression model and log-rank test were used to identify independent predictors of prognosis. TBX5 was silenced or downregulated in 88% (7/8) colon cancer cell lines, but was expressed in normal colon tissues. Loss of gene expression was associated with promoter methylation. The biological function of TBX5 in human colon cancer cells was examined. Re-expression of TBX5 in silenced colon cancer cell lines suppressed colony formation (Po0.001), proliferation (Po0.001), migration and induced apoptosis (Po0.01). Induction of apoptosis was mediated through cross-talk of extrinsic apoptosis pathway, apoptotic BCL2-associated X protein and Granzyme A signaling cascades. TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. TBX5 methylation was detected in 68% (71/105) of primary colon tumors. Multivariate analysis showed that patients with TBX5 methylation had a significantly poor overall survival (P ¼ 0.0007). In conclusion, we identified a novel functional tumor suppressor gene TBX5 inactivated by promoter methylation in colon cancer. Detection of methylated TBX5 may serve as a potential biomarker for the prognosis of this malignancy.

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Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Cited by 32 publications

References 88 publications

Distinct Expression and Function of Alternatively Spliced Tbx5 Isoforms in Cell Growth and Differentiation

Distinct Expression and Function of Alternatively Spliced Tbx5 Isoforms in Cell Growth and Differentiation

Shared gene expression profiles in developing heart valves and osteoblast progenitor cells

Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer

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