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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress
Luis Coronel1, Konstantin Riege1, Katjana Schwab1
1Computational Biology Group, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745 Jena, Germany.
Abstract:
Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7's role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.
Insights
The tumor suppressor p53 activates regulatory factor X 7 (RFX7), which controls other tumor suppressors. This p53-RFX7 pathway is crucial for cell growth, fate, and cancer prognosis.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- The tumor suppressor p53's gene regulation mechanisms are not fully understood.
- Regulatory factor X 7 (RFX7) is a newly identified suppressor of lymphoid neoplasms, but its regulatory pathways and tumor-suppressive targets are unknown.
Purpose of the Study:
- To elucidate the novel p53-RFX7 signaling axis.
- To identify RFX7's direct target genes and their role in tumor suppression.
Main Methods:
- Integrative analysis of RFX7 DNA binding landscape.
- Transcriptome analysis in three distinct cell systems.
- Correlation analysis of RFX7 target gene expression with cancer prognosis.
Main Results:
- A novel p53-RFX7 signaling axis was identified.
- RFX7 directly regulates established tumor suppressors (PDCD4, PIK3IP1, MXD4, PNRC1), acting as a link for their p53-mediated activation.
- RFX7 target gene expression correlates with better cancer prognosis and cell differentiation.
- RFX7 sensitizes cells to Doxorubicin by promoting apoptosis.
Conclusions:
- RFX7 is a ubiquitous regulator of cell growth and fate determination.
- RFX7 is a key component of the p53 transcriptional program, mediating tumor suppression through direct regulation of multiple target genes.
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