scholarly journals Transcription of the Geminin gene is regulated by a negative-feedback loop

2014 ◽  
Vol 25 (8) ◽  
pp. 1374-1383 ◽  
Author(s):  
Yoshinori Ohno ◽  
Keita Saeki ◽  
Shin'ichiro Yasunaga ◽  
Toshiaki Kurogi ◽  
Kyoko Suzuki-Takedachi ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Transcriptional Activation ◽  
Feedback Loop ◽  
Cellular Proliferation ◽  
Histone H3 ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Negative Feedback Loop ◽  
Histone H2a ◽  
Central Function

Geminin performs a central function in regulating cellular proliferation and differentiation in development and also in stem cells. Of interest, down-regulation of Geminin induces gene transcription regulated by E2F, indicating that Geminin is involved in regulation of E2F-mediated transcriptional activity. Because transcription of the Geminin gene is reportedly regulated via an E2F-responsive region (E2F-R) located in the first intron, we first used a reporter vector to examine the effect of Geminin on E2F-mediated transcriptional regulation. We found that Geminin transfection suppressed E2F1- and E2F2-mediated transcriptional activation and also mildly suppressed such activity in synergy with E2F5, 6, and 7, suggesting that Geminin constitutes a negative-feedback loop for the Geminin promoter. Of interest, Geminin also suppressed nuclease accessibility, acetylation of histone H3, and trimethylation of histone H3 at lysine 4, which were induced by E2F1 overexpression, and enhanced tri­methylation of histone H3 at lysine 27 and monoubiquitination of histone H2A at lysine 119 in E2F-R. However, Geminin5EQ, which does not interact with Brahma or Brg1, did not suppress accessibility to nuclease digestion or transcription but had an overall dominant-negative effect. These findings suggest that E2F-mediated activation of Geminin transcription is negatively regulated by Geminin through the inhibition of chromatin remodeling.

scholarly journals A negative feedback loop at the nuclear periphery regulates GAL gene expression

2012 ◽  
Vol 23 (7) ◽  
pp. 1367-1375 ◽  
Author(s):  
Erin M. Green ◽  
Ying Jiang ◽  
Ryan Joyner ◽  
Karsten Weis
Keyword(s):  
Gene Expression ◽  
Negative Feedback ◽  
Transcriptional Activation ◽  
Feedback Loop ◽  
Nuclear Periphery ◽  
Gene Interaction ◽  
Nuclear Pore ◽  
Negative Feedback Loop ◽  
Gating Model ◽  
Gene Positioning

The genome is nonrandomly organized within the nucleus, but it remains unclear how gene position affects gene expression. Silenced genes have frequently been found associated with the nuclear periphery, and the environment at the periphery is believed to be refractory to transcriptional activation. However, in budding yeast, several highly regulated classes of genes, including the GAL7-10-1 gene cluster, are known to translocate to the nuclear periphery concurrent with their activation. To investigate the role of gene positioning on GAL gene expression, we monitored the effects of mutations that disrupt the interaction between the GAL locus and the periphery or synthetically tethered the locus to the periphery. Localization to the nuclear periphery was found to dampen initial GAL gene induction and was required for rapid repression after gene inactivation, revealing a function for the nuclear periphery in repressing endogenous GAL gene expression. Our results do not support a gene-gating model in which GAL gene interaction with the nuclear pore ensures rapid gene expression, but instead they suggest that a repressive environment at the nuclear periphery establishes a negative feedback loop that enables the GAL locus to respond rapidly to changes in environmental conditions.

scholarly journals Human ΔNp73 regulates a dominant negative feedback loop for TAp73 and p53

2001 ◽  
Vol 8 (12) ◽  
pp. 1213-1223 ◽  
Author(s):  
T J Grob ◽  
U Novak ◽  
C Maisse ◽  
D Barcaroli ◽  
A U Lüthi ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Dominant Negative ◽  
Negative Feedback Loop

scholarly journals Negative Feedback Loop of Wnt Signaling through Upregulation of Conductin/Axin2 in Colorectal and Liver Tumors

2002 ◽  
Vol 22 (4) ◽  
pp. 1184-1193 ◽  
Author(s):  
Barbara Lustig ◽  
Boris Jerchow ◽  
Martin Sachs ◽  
Sigrid Weiler ◽  
Torsten Pietsch ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Time Course ◽  
Liver Tumors ◽  
Wnt Signaling Pathway ◽  
Dominant Negative ◽  
Negative Regulator ◽  
Dominant Negative Mutant ◽  
Negative Feedback Loop

ABSTRACT Activation of Wnt signaling through β-catenin/TCF complexes is a key event in the development of various tumors, in particular colorectal and liver tumors. Wnt signaling is controlled by the negative regulator conductin/axin2/axil, which induces degradation of β-catenin by functional interaction with the tumor suppressor APC and the serine/threonine kinase GSK3β. Here we show that conductin is upregulated in human tumors that are induced by β-catenin/Wnt signaling, i.e., high levels of conductin protein and mRNA were found in colorectal and liver tumors but not in the corresponding normal tissues. In various other tumor types, conductin levels did not differ between tumor and normal tissue. Upregulation of conductin was also observed in the APC-deficient intestinal tumors of Min mice. Inhibition of Wnt signaling by a dominant-negative mutant of TCF downregulated conductin but not the related protein, axin, in DLD1 colorectal tumor cells. Conversely, activation of Wnt signaling by Wnt-1 or dishevelled increased conductin levels in MDA MB 231 and Neuro2A cells, respectively. In time course experiments, stabilization of β-catenin preceded the upregulation of conductin by Wnt-1. These results demonstrate that conductin is a target of the Wnt signaling pathway. Upregulation of conductin may constitute a negative feedback loop that controls Wnt signaling activity.

scholarly journals E2f1, E2f2, and E2f3 Control E2F Target Expression and Cellular Proliferation via a p53-Dependent Negative Feedback Loop

2012 ◽  
Vol 32 (9) ◽  
pp. 1758-1758
Author(s):  
C. Timmers ◽  
N. Sharma ◽  
R. Opavsky ◽  
B. Maiti ◽  
L. Wu ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Cellular Proliferation ◽  
Negative Feedback Loop

A miR-29a-driven negative feedback loop regulates the glucocorticoid receptor in health and disease

2018 ◽  
Author(s):  
C Glantschnig ◽  
M Koenen ◽  
M Gil Lozano ◽  
M Karbiener ◽  
CL Cummins ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Health And Disease

scholarly journals Dominant Negative Mutants Implicate STAT5 in Myeloid Cell Proliferation and Neutrophil Differentiation

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4154-4166 ◽  
Author(s):  
Robert L. Ilaria ◽  
Robert G. Hawley ◽  
Richard A. Van Etten
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Cytokine Signaling ◽  
Transactivation Domain ◽  
Negative Effects ◽  
Murine Bone Marrow ◽  
Negative Effect

Abstract STAT5 is a member of the signal transducers and activation of transcription (STAT) family of latent transcription factors activated in a variety of cytokine signaling pathways. We introduced alanine substitution mutations in highly conserved regions of murine STAT5A and studied the mutants for dimerization, DNA binding, transactivation, and dominant negative effects on erythropoietin-induced STAT5-dependent transcriptional activation. The mutations included two near the amino-terminus (W255KR→AAA and R290QQ→AAA), two in the DNA-binding domain (E437E→AA and V466VV→AAA), and a carboxy-terminal truncation of STAT5A (STAT5A/▵53C) analogous to a naturally occurring isoform of rat STAT5B. All of the STAT mutant proteins were tyrosine phosphorylated by JAK2 and heterodimerized with STAT5B except for the WKR mutant, suggesting an important role for this region in STAT5 for stabilizing dimerization. The WKR, EE, and VVV mutants had no detectable DNA-binding activity, and the WKR and VVV mutants, but not EE, were defective in transcriptional induction. The VVV mutant had a moderate dominant negative effect on erythropoietin-induced STAT5 transcriptional activation, which was likely due to the formation of heterodimers that are defective in DNA binding. Interestingly, the WKR mutant had a potent dominant negative effect, comparable to the transactivation domain deletion mutant, ▵53C. Stable expression of either the WKR or ▵53C STAT5 mutants in the murine myeloid cytokine-dependent cell line 32D inhibited both interleukin-3–dependent proliferation and granulocyte colony-stimulating factor (G-CSF)–dependent differentiation, without induction of apoptosis. Expression of these mutants in primary murine bone marrow inhibited G-CSF–dependent granulocyte colony formation in vitro. These results demonstrate that mutations in distinct regions of STAT5 exert dominant negative effects on cytokine signaling, likely through different mechanisms, and suggest a role for STAT5 in proliferation and differentiation of myeloid cells.

scholarly journals Smad2/3 Activation Regulates Smad1/5/8 Signaling via a Negative Feedback Loop to Inhibit 3T3-L1 Adipogenesis

2021 ◽  
Vol 22 (16) ◽  
pp. 8472
Author(s):  
Senem Aykul ◽  
Jordan Maust ◽  
Vijayalakshmi Thamilselvan ◽  
Monique Floer ◽  
Erik Martinez-Hackert
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Adipose Tissues ◽  
Family Growth ◽  
Simultaneous Activation ◽  
Adipocyte Hypertrophy ◽  
Adipocyte Development ◽  
Energy Surplus

Adipose tissues (AT) expand in response to energy surplus through adipocyte hypertrophy and hyperplasia. The latter, also known as adipogenesis, is a process by which multipotent precursors differentiate to form mature adipocytes. This process is directed by developmental cues that include members of the TGF-β family. Our goal here was to elucidate, using the 3T3-L1 adipogenesis model, how TGF-β family growth factors and inhibitors regulate adipocyte development. We show that ligands of the Activin and TGF-β families, several ligand traps, and the SMAD1/5/8 signaling inhibitor LDN-193189 profoundly suppressed 3T3-L1 adipogenesis. Strikingly, anti-adipogenic traps and ligands engaged the same mechanism of action involving the simultaneous activation of SMAD2/3 and inhibition of SMAD1/5/8 signaling. This effect was rescued by the SMAD2/3 signaling inhibitor SB-431542. By contrast, although LDN-193189 also suppressed SMAD1/5/8 signaling and adipogenesis, its effect could not be rescued by SB-431542. Collectively, these findings reveal the fundamental role of SMAD1/5/8 for 3T3-L1 adipogenesis, and potentially identify a negative feedback loop that links SMAD2/3 activation with SMAD1/5/8 inhibition in adipogenic precursors.

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