scholarly journals Activating Transcription Factor 1 and CREB Are Important for Cell Survival during Early Mouse Development

2002 ◽  
Vol 22 (6) ◽  
pp. 1919-1925 ◽  
Author(s):  
Susanne C. Bleckmann ◽  
Julie A. Blendy ◽  
Dorothea Rudolph ◽  
A. Paula Monaghan ◽  
Wolfgang Schmid ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Mouse Development ◽  
Camp Response Element ◽  
Basic Leucine Zipper ◽  
Response Element ◽  
Activating Transcription Factor ◽  
Early Mouse ◽  
Transcription Factor 1

ABSTRACT Activating transcription factor 1 (ATF1), CREB, and the cyclic AMP (cAMP) response element modulatory protein (CREM), which constitute a subfamily of the basic leucine zipper transcription factors, activate gene expression by binding as homo- or heterodimers to the cAMP response element in regulatory regions of target genes. To investigate the function of ATF1 in vivo, we inactivated the corresponding gene by homologous recombination. In contrast to CREB-deficient mice, which suffer from perinatal lethality, mice lacking ATF1 do not exhibit any discernible phenotypic abnormalities. Since ATF1 and CREB but not CREM are strongly coexpressed during early mouse development, we generated mice deficient for both CREB and ATF1. ATF1−/− CREB−/− embryos die before implantation due to developmental arrest. ATF1+/− CREB−/− embryos display a phenotype of embryonic lethality around embryonic day 9.5 due to massive apoptosis. These results indicate that CREB and ATF1 act in concert to mediate signals essential for maintaining cell viability during early embryonic development.

scholarly journals MAPK-directed activation of the whitefly transcription factor CREB leads to P450-mediated imidacloprid resistance

2020 ◽  
Vol 117 (19) ◽  
pp. 10246-10253 ◽  
Author(s):  
Xin Yang ◽  
Shun Deng ◽  
Xuegao Wei ◽  
Jing Yang ◽  
Qiannan Zhao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathway ◽  
Gene Families ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Bzip Transcription Factor ◽  
Camp Response Element ◽  
Response Element

The evolution of insect resistance to pesticides poses a continuing threat to agriculture and human health. While much is known about the proximate molecular and biochemical mechanisms that confer resistance, far less is known about the regulation of the specific genes/gene families involved, particularly by trans-acting factors such as signal-regulated transcription factors. Here we resolve in fine detail the trans-regulation of CYP6CM1, a cytochrome P450 that confers resistance to neonicotinoid insecticides in the whitefly Bemisia tabaci, by the mitogen-activated protein kinase (MAPK)-directed activation of the transcription factor cAMP-response element binding protein (CREB). Reporter gene assays were used to identify the putative promoter of CYP6CM1, but no consistent polymorphisms were observed in the promoter of a resistant strain of B. tabaci (imidacloprid-resistant, IMR), which overexpresses this gene, compared to a susceptible strain (imidacloprid-susceptible, IMS). Investigation of potential trans-acting factors using in vitro and in vivo assays demonstrated that the bZIP transcription factor CREB directly regulates CYP6CM1 expression by binding to a cAMP-response element (CRE)-like site in the promoter of this gene. CREB is overexpressed in the IMR strain, and inhibitor, luciferase, and RNA interference assays revealed that a signaling pathway of MAPKs mediates the activation of CREB, and thus the increased expression of CYP6CM1, by phosphorylation-mediated signal transduction. Collectively, these results provide mechanistic insights into the regulation of xenobiotic responses in insects and implicate both the MAPK-signaling pathway and a transcription factor in the development of pesticide resistance.

scholarly journals Activity of the Yap1 Transcription Factor in Saccharomyces cerevisiae Is Modulated by Methylglyoxal, a Metabolite Derived from Glycolysis

2004 ◽  
Vol 24 (19) ◽  
pp. 8753-8764 ◽  
Author(s):  
Kazuhiro Maeta ◽  
Shingo Izawa ◽  
Shoko Okazaki ◽  
Shusuke Kuge ◽  
Yoshiharu Inoue
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcription Factor ◽  
Disulfide Bond ◽  
Target Genes ◽  
Cysteine Residue ◽  
Cysteine Residues ◽  
Glyoxalase I ◽  
Toxic Metabolite ◽  
Basic Leucine Zipper

ABSTRACT Methylglyoxal (MG) is synthesized during glycolysis, although it inhibits cell growth in all types of organisms. Hence, it has long been asked why such a toxic metabolite is synthesized in vivo. Glyoxalase I is a major enzyme detoxifying MG. Here we show that the Yap1 transcription factor, which is critical for the oxidative-stress response in Saccharomyces cerevisiae, is constitutively concentrated in the nucleus and activates the expression of its target genes in a glyoxalase I-deficient mutant. Yap1 contains six cysteine residues in two cysteine-rich domains (CRDs), i.e., three cysteine residues clustering near the N terminus (n-CRD) and the remaining three cysteine residues near the C terminus (c-CRD). We reveal that any of the three cysteine residues in the c-CRD is sufficient for MG to allow Yap1 to translocate into the nucleus and to activate the expression of its target gene. A Yap1 mutant possessing only one cysteine residue in the c-CRD but no cysteine in the n-CRD and deletion of the basic leucine zipper domain can concentrate in the nucleus with MG treatment. However, substitution of all the cysteine residues in Yap1 abolishes the ability of this transcription factor to concentrate in the nucleus following MG treatment. The redox status of Yap1 is substantially unchanged, and protein(s) interaction with Yap1 through disulfide bond is hardly detected in cells treated with MG. Collectively, neither intermolecular nor intramolecular disulfide bond formation seems to be involved in Yap1 activation by MG. Moreover, we show that nucleocytoplasmic localization of Yap1 closely correlates with growth phase and intracellular MG level. We propose a novel regulatory pathway underlying Yap1 activation by a natural metabolite in the cell.

The Role of GM-CSF Signaling and CREB in Myeloid Proliferation and Survival.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-33-sci-33
Author(s):  
Kathleen M. Sakamoto
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Target Genes ◽  
Critical Role ◽  
Myeloid Cells ◽  
Camp Response Element ◽  
Response Element ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Myeloid Progenitor

Abstract Normal myelopoiesis is regulated by the delicate interplay between hematopoietic stem cells (HSCs) and the bone marrow microenvironment. Through the action of hematopoietic growth factors and their receptors, alterations of transcriptional regulation result in myeloid progenitor cell proliferation and survival. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Interleukin-3 (IL-3) are cytokines that regulate myelopoiesis. GMCSF and IL-3 induce signaling pathways that activate serine threonine kinases, including MEK, ERK, and pp90RSK, leading to expression of immediate early genes such as early growth response gene-1 (egr-1). Analysis of promoter regions of egr-1 demonstrated that the cAMP response element, CRE, was necessary and sufficient for egr-1 expression in myeloid cells. We previously demonstrated that the transcription factor, CREB (cAMP Response Element Binding Protein), recognizes the CRE in the egr-1 promoter and is phosphorylated at serine 133 in response to GM-CSF and IL-3 through a MEK-dependent, protein kinase A-independent pathways. CREB is a leucine zipper transcription factor that regulates proliferation, differentiation, and survival of neuronal cells and lymphocytes. The majority of patients with acute lymphoid and myeloid leukemias express higher levels of CREB in their bone marrow. Therefore, we hypothesized that CREB plays a critical role in the regulation of normal hematopoiesis. To this end, we studied the biological and molecular effects of CREB in myeloid cells. CREB overexpression results in increased proliferation and survival through induction of cyclin A1 and other target genes. Transgenic mice that overexpress CREB in Gr-1/Mac-1+ cells develop myeloproliferative disease after one year. Knockdown of CREB using shRNAs leads to decreased proliferation and differentiation of myeloid progenitor cells and increased apoptosis of HSCs. Cell cycle analysis demonstrate that CREB downregulation in HSCs leads to greater numbers of cells in G1 and fewer cells in S phase. Both cyclin D1 and A1 levels are decreased in CREB shRNA-transduced HSCs. However, CREB knockdown of bone marrow progenitors did not affect long-term engraftment in transplantation assays. Recent findings on downstream pathways of CREB and potential target genes will be presented.

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