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A computerized database-scan to identify c-MYC targets
Oren Schuldiner1, Sharon Shor, Nissim Benvenisty
1Department of Genetics, The Silberman Institute for Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel.
Abstract:
The c-MYC oncogene plays a pivotal role in the malignant transformation of various types of human cancer. It is also a key regulator of cellular proliferation, embryonic differentiation and apoptosis. c-MYC encodes a transcription factor that activates target genes in a sequence specific manner through heterodimerization with the ubiquitously expressed factor MAX. Identifying c-MYC target genes is therefore crucial for elucidating the molecular pathways that are downstream of MYC. Most of the c-MYC targets isolated to date as well as targets of other transcription factors have been identified by differential expression or the candidate gene approach. In this paper, we outline a computer-based scan that allows us to create a pool of putative target genes for a transcription factor. The scan is based on a set of criteria including sequence specificity of the c-MYC transcription factor, sequence location and evolutionary conservation of these regulatory elements. Using this procedure, we have identified 12 putative targets for c-MYC. Expression analyses, DNA binding assays and chimeric promoter-reporter experiments suggest that two genes, NM23-H2 and N-RAS, may indeed be direct targets for c-MYC activation. This type of computer-based scan may have a general use to identify targets for other transcription factors.
Insights
A new computational method identifies potential target genes for the c-MYC oncogene. This approach, focusing on sequence specificity and conservation, found 12 candidates, with NM23-H2 and N-RAS showing promise as direct targets.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The c-MYC oncogene is crucial in human cancer development, regulating cell proliferation, differentiation, and apoptosis.
- c-MYC functions as a transcription factor, binding DNA sequence-specifically after forming a heterodimer with MAX.
- Identifying c-MYC target genes is essential for understanding downstream molecular pathways in cancer.
Purpose of the Study:
- To develop and validate a computational method for identifying putative transcription factor target genes.
- To identify novel target genes regulated by the c-MYC transcription factor.
Main Methods:
- A computer-based scan was designed using criteria such as sequence specificity, location, and evolutionary conservation of regulatory elements.
- The scan identified a pool of 12 putative c-MYC target genes.
- Expression analyses, DNA binding assays, and reporter gene experiments were performed to validate potential targets.
Main Results:
- The computational scan successfully identified 12 putative target genes for c-MYC.
- Expression analyses and functional assays indicated that NM23-H2 and N-RAS are likely direct targets of c-MYC activation.
- The study validated the efficacy of the computational approach in predicting transcription factor targets.
Conclusions:
- A novel computational strategy effectively identifies putative transcription factor target genes.
- NM23-H2 and N-RAS are proposed as direct c-MYC targets, offering new insights into MYC-driven oncogenesis.
- This computer-based scanning method has broad applicability for discovering targets of other transcription factors.