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Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
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Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
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Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
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Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
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General Transcription Factors

Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...

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Induction and Analysis of Epithelial to Mesenchymal Transition
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Transcription factor interactions mediate EGF-dependent COX-2 expression.

Kaiming Xu1, Hui-Kuo G Shu

  • 1Department of Radiation Oncology, Emory University, 1365 Clifton Road, NE, Suite CT-104, Atlanta, GA 30322, USA.

Molecular Cancer Research : MCR
|May 3, 2013
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Epidermal growth factor receptor (EGFR) signaling induces Cyclooxygenase-2 (COX-2) in gliomas. FOXM1 and Sp1 transcription factors cooperate on the COX-2 promoter, mediating this crucial induction for potential therapeutic targets.

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Area of Science:

  • Molecular Oncology
  • Cancer Signaling Pathways
  • Gene Regulation

Background:

  • Cyclooxygenase-2 (COX-2) expression correlates with poor prognosis in malignant glioma patients.
  • Epidermal growth factor receptor (EGFR) amplification/overexpression is frequent in gliomas.
  • EGFR signaling activates the p38-MAPK/PKC-δ/Sp1 cascade, regulating COX-2 expression.

Purpose of the Study:

  • To elucidate the upstream signaling molecules involved in EGFR-mediated COX-2 induction in glioma.
  • To investigate the role of FOXM1 in the regulation of COX-2 expression by EGF.
  • To define the precise mechanism of FOXM1 and Sp1 interaction in mediating COX-2 induction.

Main Methods:

  • Analysis of signaling cascades upstream of COX-2.
  • Investigation of FOXM1 protein levels and function upon EGF stimulation.
  • Reporter assays and promoter analysis to define transcription factor binding sites and interactions.

Main Results:

  • Src kinase acts upstream in the EGFR-mediated signaling cascade.
  • EGF stimulation increases FOXM1 protein levels, but its role in COX-2 induction is independent of this increase.
  • FOXM1 cooperates with Sp1 at a specific promoter site (-245/-240) to mediate EGF-induced COX-2 expression, bypassing a distal FOXM1 element.

Conclusions:

  • A novel interaction between FOXM1 and Sp1 at the COX-2 promoter is identified as the key mechanism for EGF-induced COX-2 expression.
  • This finding clarifies the mechanistic basis of EGFR's role in glioma COX-2 regulation.
  • The identified pathway offers potential therapeutic targets for malignant gliomas.