The c-Jun δ-Domain Inhibits Neuroendocrine Promoter Activity in a DNA Sequence- and Pituitary-specific Manner

Farrow, Kathryn N.; Manning, Nicole; Schaufele, Fred; Gutierrez‐Hartmann, Arthur

doi:10.1074/jbc.271.29.17139

Cited by 23 publications

(14 citation statements)

References 55 publications

(88 reference statements)

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“…(DEI) 4-alb-LUC construct, used to evaluate NF-IL-6 activity was kindly provided by Dr. P. Johnson and consists of CCAAT/enhancer-binding protein (C/EBP) responsive DEI sites and an albumin minimal promoter coupled to the luciferase (LUC) gene (26). The LUC reporter gene under the control of 2.5 kb of the PRL promoter (PRL-LUC) construct was provided by Dr. A. Gutierrez-Hartmann (27).…”

Section: Constructsmentioning

confidence: 99%

Reduced Expression of the Cytokine Transducer gp130 Inhibits Hormone Secretion, Cell Growth, and Tumor Development of Pituitary Lactosomatotrophic GH3 Cells

et al. 2003

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Two of the most potent cytokines that regulate anterior pituitary cell function are leukemia inhibitory factor and IL-6. These and others like IL-11 and ciliary neurotrophic factor are referred to as the gp130 cytokines because they share the gp130 glycoprotein as a common receptor initial signal transducer. We and others have shown that gp130 cytokines and their receptors are expressed and functional in normal and tumoral anterior pituitary cells. To study the role of gp130 cytokines in tumorigenic process, we generated gp130 cDNA gp130 sense and gp130 antisense (gp130-AS) transfected stable clones derived from lactosomatotroph GH3 cells. We examined hormone secretion and cell proliferation of these clones as well as their tumorigenic properties in athymic nude mice. Although gp130-AS clones, which have low gp130 levels and impaired signal transducer and activator of transcription 3 activity and suppressor of cytokine signaling-3 expression, showed reduced proliferation and hormone secretion (GH and prolactin) in response to gp130 cytokines, they had a normal response to gp130-independent stimuli. Moreover, gp130-AS clones showed a severely impaired in vivo tumor development. In contrast, the overexpressing gp130 clones (gp130 sense) showed no differences, compared with cells transfected with control vector. Thus, the present study provides new evidence supporting a link between gp130 and pituitary abnormal growth.

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Section: Constructsmentioning

confidence: 99%

Reduced Expression of the Cytokine Transducer gp130 Inhibits Hormone Secretion, Cell Growth, and Tumor Development of Pituitary Lactosomatotrophic GH3 Cells

et al. 2003

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“…Combinatorial interactions between Pit-1 and other trans-acting factors at composite or adjacent response elements have been shown to allow Pit-1 to serve as a cell-specific integrator of signaling pathways. As such, Pit-1 has been shown to physically interact with itself, ER, 1 thyroid hormone receptor, c-Jun, Oct-1, GATA-2, P-Lim, Ptx-1, and Ets-1 (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Ras Signaling and Transcriptional Synergy at a Flexible Ets-1/Pit-1 Composite DNA Element Is Defined by the Assembly of Selective Activation Domains

Duval

Jean

Gutierrez‐Hartmann

2003

Journal of Biological Chemistry

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Pit-1 and Ets-1 binding to a composite element synergistically activates and targets Ras-mitogen-activated protein kinase signaling to the rat prolactin promoter. These transcriptional responses appear to depend on three molecular features: organization of the Ets-1/Pit-1 composite element, physical interaction of these two factors via the Pit-1 homeodomain (amino acids 199 -291) and the Ets-1 regulatory III domain (amino acids 190 -257), and assembly of their transcriptional activation domains (TADs). Here we show that the organization of the Ets-1/Pit-1 composite element tolerates significant flexibility with regard to Ras stimulation and synergy. Specifically, the putative monomeric Pit-1 binding site can be substituted with bona fide binding sites for either a Pit-1 monomer or dimer, and these sites tolerated a separation of 28 bp. Additionally, we show that the physical interaction of Ets-1 and Pit-1 is not required for Ras responsiveness or synergy because block mutations of the Pit-1 interaction surface in Ets-1, which reduced Ets-1/Pit-1 binding in vitro, did not significantly affect Ets-1 stimulation of Ras responsiveness or synergy. We also show differential use of distinct TAD subtypes and Pit-1 TAD subregions to mediate either synergy or Ras responsiveness. Specifically, TADs from Gal4, VP16, or Ets-2 regulatory III domain linked to Ets-1 DNA binding domain constructs restored synergy to these TAD/Ets-1 DNA binding domain fusions. Conversely, deletion of the defined Pit-1 TAD (amino acids 2-80) retained synergy, but not Ras responsiveness. Consequently, we further defined the Pit-1 amino-terminal TAD into region 1 (R1, amino acids 2-45) and region 2 (R2, amino acids 46 -80). R1 appears to regulate basal and synergistic responses, whereas the Ras response was mapped to R2. In summary, Ras responsiveness and Pit-1/Ets-1 synergy are mediated through the assembly of distinct TADs at a flexible composite element, indicating that different mechanisms underlie these two transcriptional responses and that the Pit-1 R2 subregion represents a novel, tissue-specific Ras-responsive TAD.

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“…c-Jun has been found to be up-regulated in response to inflammation [Raivich, 2008] and to participate in the suppression of the promoter activity of several inflammatory genes [Afonso et al, 2006; Bois-Joyeux et al, 1995; Drosatos et al, 2007; Farrow et al, 1996; Franklin et al, 1995; Hadzopoulou-Cladaras et al, 1998; Matsuguchi et al, 2003; Wang et al, 2000]. c-Jun physically interacts with Sp1 [Chen and Chang, 2000; Kardassis et al, 1999; Wu et al, 2003], and this interaction has been shown to either enhance or repress the expression of target genes [Chen and Chang, 2000; Kardassis et al, 1999; Yuan et al, 2010].…”

Section: Discussionmentioning

confidence: 99%

“…Previous data revealed that c-Jun is activated during inflammation [Raivich, 2008]. It participates in the suppression of the promoter activity of several inflammatory genes [Afonso et al, 2006; Bois-Joyeux et al, 1995; Drosatos et al, 2007; Farrow et al, 1996; Franklin et al, 1995; Hadzopoulou-Cladaras et al, 1998; Matsuguchi et al, 2003; Wang et al, 2000]. In the present study, we found that (1) an AP-1-like binding site is required for LPS to repress the activity of the MFG-E8 gene promoter; and (2) over-expression of c-Jun results in the down-regulation of the MFG-E8 gene promoter activity.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Underlying the Regulation of the MFG‐E8 Gene Promoter Activity in Physiological and Inflammatory Conditions

Wang

Liu

et al. 2015

J of Cellular Biochemistry

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Milk fat globule-EGF factor 8 (MFG-E8) is expressed by macrophages and plays an important role in attenuating inflammation and maintaining tissue homeostasis. Previously, we and others found that LPS inhibits MFG-E8 gene expression in macrophages. Here, we characterized the 5′-flanking region of the mouse MFG-E8 gene. To functionally analyze the upstream regulatory region of the MFG-E8 gene, a series of luciferase reporter gene constructs containing deleted or mutated regulatory elements were prepared. Using the luciferase assay, we revealed that Sp1 binding motifs within the proximal promoter region were necessary for full activity of the MFG-E8 promoter, whereas AP-1 like binding sequence at −372 played a role in governing the promoter activity at a homeostatic level. With chromatin immunoprecipitation assay, we showed that Sp1 and c-Jun physically interact with the MFG-E8 promoter region in vivo. In addition, Sp1 was found to regulate the MFG-E8 promoter activity positively and c-Jun negatively. Furthermore, we demonstrated that LPS inhibited MFG-E8 promoter activity via targeting Sp1 and AP-1-like motifs in the 5′-flanking region. Collectively, our data indicate that Sp1 and AP-1-related factors are involved in the regulation of MFG-E8 gene transcription by targeting their binding sites in the 5′-flanking region under physiological and inflammatory states.

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The c-Jun δ-Domain Inhibits Neuroendocrine Promoter Activity in a DNA Sequence- and Pituitary-specific Manner

Cited by 23 publications

References 55 publications

Reduced Expression of the Cytokine Transducer gp130 Inhibits Hormone Secretion, Cell Growth, and Tumor Development of Pituitary Lactosomatotrophic GH3 Cells

Reduced Expression of the Cytokine Transducer gp130 Inhibits Hormone Secretion, Cell Growth, and Tumor Development of Pituitary Lactosomatotrophic GH3 Cells

Ras Signaling and Transcriptional Synergy at a Flexible Ets-1/Pit-1 Composite DNA Element Is Defined by the Assembly of Selective Activation Domains

Molecular Mechanisms Underlying the Regulation of the MFG‐E8 Gene Promoter Activity in Physiological and Inflammatory Conditions

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