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Cutting the chain of command: specific inhibitors of transcription
1Department of Cell Biology, Vanderbilt University, Nashville, Tennessee.
Abstract:
Cell growth and differentiation are regulated (at least in part) by changes in gene transcription. The cloning and characterization of transcription factors has revealed that these factors coordinately regulate the transcription of specific genetic programs; for example, a number of phorbol ester-induced genes are activated by binding of the transcription factors Fos and Jun to specific DNA sequences. Clearly, inhibition of either the production or function of specific transcription factors would alter complete genetic programs, changing the expression of a great number of genes (analogous to cutting the chain of military command and affecting an entire brigade or division). Our laboratory and others have employed genetic methods to specifically inhibit transcription by two distinct methods: (1) antisense inhibition of the production of transcription factors; and (2) introduction of target DNA sequences to "soak up"or quench transcription factors. In this report, we present data showing that serum-stimulated induction of the c-fos gene may be reduced more than 90% by introduction of target DNA sequences containing the serum response element (SRE); identical amounts of mutant SRE sequences have no effect on gene induction. These studies demonstrate that specific inhibitors of transcription can have significant effects on cellular gene expression. The challenge is to modulate transcriptional programs without deleterious effects on normal cells.
Insights
Researchers used DNA sequences to block transcription factors, significantly reducing c-fos gene induction. This demonstrates a method to control gene expression by inhibiting specific transcription factors.
Area of Science:
- Molecular Biology
- Genetics
Background:
- Cellular processes like growth and differentiation rely on gene transcription regulation.
- Transcription factors, such as Fos and Jun, control specific genetic programs by binding to DNA sequences.
- Inhibiting transcription factors can broadly affect gene expression, impacting entire genetic programs.
Purpose of the Study:
- To investigate methods for specifically inhibiting transcription factors.
- To demonstrate the effectiveness of using target DNA sequences to modulate gene transcription.
Main Methods:
- Employing genetic methods to inhibit transcription.
- Utilizing antisense inhibition to reduce transcription factor production.
- Introducing target DNA sequences (serum response element - SRE) to sequester transcription factors.
Main Results:
- Serum-stimulated induction of the c-fos gene was reduced by over 90% using SRE-containing DNA sequences.
- Mutant SRE sequences did not affect gene induction, confirming the specificity of the method.
Conclusions:
- Specific inhibitors of transcription can significantly impact cellular gene expression.
- Modulating transcriptional programs offers a potential strategy for controlling cellular processes.
- The challenge lies in achieving targeted transcriptional modulation without adverse effects on normal cells.