A Novel Activation Function for NAB Proteins in EGR-dependent Transcription of the Luteinizing Hormone β Gene

Sevetson, Bradley R.; Svaren, John; Milbrandt, Jeffrey

doi:10.1074/jbc.275.13.9749

Cited by 88 publications

(90 citation statements)

References 62 publications

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“…The Ϫ1523 to ϩ23 TRAIL promoter luciferase reporter deletion plasmids were described previously (37). Luciferase reporter assays were performed as described (38,39). Mutation of the forkhead binding site in the Ϫ165 to ϩ23 TRAIL promoter luciferase construct was generated using the QuikChange kit (Stratagene Corp.) and complementary primers 5Ј-GAGGAGCTTCA-GACAGAGACCCTCCAGACCAACGCCAACG-3Ј and CGTTGGCGTT-GGTCTGGAGGGTCTCTGTCTGAAGCTCCTC.…”

Section: Methodsmentioning

confidence: 99%

FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression

Modur

Nagarajan

Evers

et al. 2002

Journal of Biological Chemistry

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340

299

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Mutations in PTEN occur in 60 -80% of prostate cancers and lead to a constitutive activation of the phosphatidylinositol 3-kinase pathway and a resultant loss of activity of the FOXO family of forkhead transcription factors FKHRL1 and FKHR. To provide insight into the role of PTEN mutations in prostate cancer, we used microarrays to identify genes regulated by FKHRL1 and FKHR in LAPC4 prostate carcinoma cells. These studies revealed that adenoviral overexpression of FKHRL1 and FKHR in the LAPC4 prostate cancer cell line resulted in apoptosis and induced the expression of many genes that affect cellular proliferation or survival. The expression of one of these FOXO-regulated genes, TRAIL, a pro-apoptotic member of the tumor necrosis factor family, was decreased in human metastatic prostate tumors. The altered expression of TRAIL in these tumors correlated directly with decreased PTEN expression and the resultant loss of FKHRL1 and FKHR activity. Analysis of the effects of FOXO proteins on the TRAIL promoter localized the FKHRL1 responsive element of the TRAIL promoter to nucleotides ؊138 to ؊121 and demonstrated that TRAIL is a direct target of FKHRL1. These findings suggest that the decreased activity of FKHRL1 and FKHR in prostate cancers resulting from loss of PTEN leads to a decrease in TRAIL expression that may contribute to increased survival of the tumor cells.The forkhead transcription factors are DNA-binding proteins characterized by the presence of a conserved 110-amino acid winged helix DNA binding domain (1). They play important roles in embryogenesis, tumorigenesis, and maintenance of differentiation status. In Caenorhabditis elegans the forkhead transcription factor DAF-16 is under control of the insulin receptor/PI 3-kinase 1 pathway (2). The human orthologs of DAF-16 include FKHRL1, FKHR, and AFX and belong to the FOXO subfamily of forkhead transcription factors. The PI 3-kinase pathway, via activation of its downstream kinase Akt, phosphorylates each of the FOXO proteins at three different Ser/Thr residues (3). These phosphorylated FOXO proteins interact with 14-3-3 proteins and are subsequently sequestered in the cytoplasm where they are inactive. Inhibition of the PI 3-kinase pathway by PTEN overexpression or pharmacologic means leads to dephosphorylation and nuclear translocation of active FKHRL1, FKHR, and AFX, which in turn leads to cell cycle arrest and apoptosis (4). Conversely, loss of PTEN activity results in increased Akt activity leading to inhibition of FOXO protein activity through their phosphorylation and cytoplasmic sequestration. In addition, the expression of dominant negative FKHRL1 results in the inhibition of apoptosis, demonstrating that FOXO transcriptional activity controls cellular proliferation and apoptosis downstream of PTEN (5).The PTEN gene was initially identified by its frequent loss in glioblastomas (6), but subsequent studies have shown that PTEN is commonly mutated in prostate cancer (7-12). In prostate tumors, the loss of PTEN occurs late in the tumorigenic pro...

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Section: Methodsmentioning

confidence: 99%

FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression

Modur

Nagarajan

Evers

et al. 2002

Journal of Biological Chemistry

Self Cite

340

299

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“…Originally, they were identified as corepressors of EGR-mediated transcription by direct binding to Egr-1, Egr-2 and Egr-3 [18,19]. Subsequently, it has been shown that NAB2 can also co-activate Egr-mediated transcription [20]. Indeed, our group has recently identified NAB2 as a novel co-activator of T cell function by enhancing Egr-1-mediated IL-2 production.…”

Section: Introductionmentioning

confidence: 99%

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

et al. 2008

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TCR-induced NF-AT activation leads to the up-regulation of multiple genes involved in T cell anergy. Since NF-AT is also involved in T cell activation, we have endeavored to dissect TCR-induced activating and inhibitory genetic programs. This approach revealed roles for the early growth response (Egr) family of transcription factors and the Egr coactivator/corepressor NGFI-A-binding protein (NAB)2 in regulating T cell function. TCR-induced Egr-1 and NAB2 enhance T cell function, while Egr-2 and Egr-3 inhibit T cell function. In this report, we demonstrate that Egr-2 and Egr-3 are induced by NF-AT in the absence of AP-1, while Egr-1 and NAB2 both require AP-1-mediated transcription. Our data suggest that Egr-3 is upstream of Egr-2, and that mechanistically Egr-2 and Egr-3 suppress Egr-1 and NAB2 expression. Functionally, T cells from Egr-2 and Egr-3 null mice are hyperresponsive while T cells from Egr-3 transgenic, overexpressing mice are hyporesponsive. Furthermore, an in vivo model of autoimmune pneumonitis reveals that T cells from Egr-3 null mice hasten death while Egr-3-overexpressing T cells cause less disease. Overall, our data suggest that just as the Egr/NAB network of genes control cell fate in other systems, TCR-induced Egr-1, 2, 3 and NAB2 control the fate of antigen recognition in T cells.

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“…In contrast, a specific physiologically relevant frequency range of receptor stimulation on the order of 1 pulse/h preferentially induces the luteinizing hormone beta subunit (LH␤) gene (1,2). Although downstream signal transduction mediators (such as JNK and ERK) and a number of transcription factors (including Egr1, SF1, and NAB1) have been implicated in modulation of the LH␤ promoter (3)(4)(5)(6), the available data do not explain why the induction of LH␤ requires specific patterns of GnRHR activation.…”

mentioning

confidence: 99%

Gonadotropin-releasing Hormone Receptor-coupled Gene Network Organization

Wurmbach¹,

Yuen²,

Ebersole³

et al. 2001

Journal of Biological Chemistry

169

146

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An early gene cDNA microarray was developed to study genes that are regulated immediately following gonadotropin-releasing hormone (GnRH) receptor activation. 956 selected candidate genes were printed in triplicate, a t statistic-based regulation algorithm was used for data analysis, and the response to GnRH in a time course from 1 to 6 h was determined. Measurements were highly reproducible within arrays, between arrays, and between experiments. Accuracy and algorithm reliability were established by real-time polymerase chain reaction assays of 60 genes. Gene changes ranging from 1.3-to 31-fold on the microarray were confirmed by real-time polymerase chain reaction. Many of the genes were found to be highly regulated. The regulated genes identified were all elevated at 1 h of treatment and returned nearly or completely to baseline levels of expression by 3 h of treatment. This broad, robust, and transient transcriptional response to constant GnRH exposure includes modulators of signal transduction (e.g. Rgs2 and IB), cytoskeletal proteins (e.g. ␥-actin), and transcription factors (e.g. c-Fos, Egr1, and LRG21). The interplay of the activators, repressors, and feedback inhibitors identified embodies a combinatorial code to direct the activity of specific downstream secondary genes.

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A Novel Activation Function for NAB Proteins in EGR-dependent Transcription of the Luteinizing Hormone β Gene

Cited by 88 publications

References 62 publications

FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression

FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

Gonadotropin-releasing Hormone Receptor-coupled Gene Network Organization

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