Related Experiment Video

Updated: Jul 5, 2026

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
09:58

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Published on: June 27, 2020

EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing's sarcoma

Leah A Owen1, Ashley A Kowalewski, Stephen L Lessnick

  • 1Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, United States of America.

Plos One
|April 17, 2008
PubMed

Insights

The transcription factor NKX2.2 drives Ewing sarcoma oncogenesis by repressing genes. Its DNA binding and repressor domains are essential, while its activation domain is not, suggesting therapeutic targeting of repression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • Ewing sarcoma is driven by the EWS/FLI oncoprotein, which primarily downregulates gene expression.
  • NKX2.2, a target of EWS/FLI, possesses both activation and repression domains, suggesting it may mediate EWS/FLI's effects.

Purpose of the Study:

  • To investigate the role of NKX2.2's transcriptional repressive function in Ewing sarcoma oncogenesis.
  • To determine if NKX2.2 mediates the oncogenic transcriptional signature of EWS/FLI.

Main Methods:

  • Microarray analysis to assess NKX2.2's transcriptional profile.
  • Structure-function analysis of NKX2.2 domains in Ewing sarcoma cells.
  • ChIP-chip to identify NKX2.2 genomic binding sites.
  • Assays to block TLE or HDAC function.

Main Results:

  • NKX2.2 solely downregulates genes, with a significant overlap with the EWS/FLI downregulated signature.
  • The DNA binding and repressor domains of NKX2.2 are crucial for oncogenesis, while the activation domain is dispensable.
  • Blocking TLE or HDAC function inhibited the transformed phenotype and reversed NKX2.2's transcriptional profile.
  • ChIP-chip confirmed direct NKX2.2 binding at a substantial portion of repressed genes.

Conclusions:

  • NKX2.2 mediates Ewing sarcoma oncogenesis through its transcriptional repressive function.
  • The repressive activity of NKX2.2 is both necessary and sufficient for the transformed phenotype.
  • Targeting NKX2.2's repression mechanisms offers a potential therapeutic strategy for Ewing sarcoma.

More Related Videos

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

Single-Molecule Imaging of EWS-FLI1 Condensates Assembling on DNA07:05

Single-Molecule Imaging of EWS-FLI1 Condensates Assembling on DNA

Published on: September 8, 2021

Related Concept Videos

Canonical Wnt Signaling Pathway02:54

Canonical Wnt Signaling Pathway

The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor...
Master Transcription Regulators02:23

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...
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Methods of Nuclear Reprogramming01:24

Methods of Nuclear Reprogramming

Nuclear reprogramming is a process of transforming one cell type into an unrelated cell type by epigenetic changes that alter the cell’s original gene expression pattern. Such epigenetic changes force cells to express a different set of genes, which play a significant role in inducing transformation into other cell types. Nuclear reprogramming offers applications in reproductive cloning for livestock propagation and regenerative medicine — developing patient-specific cells for injury repair.
Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal01:22

Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal

Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.