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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
CYFIP2, a direct p53 target, is leptomycin-B sensitive
Roger S Jackson1, Yong-Jig Cho, Susanne Stein
1Vanderbilt-Ingram Comprehensive Cancer Center, Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6840, USA.
Abstract:
A number of target genes for the tumor suppressor, p53, have been identified, however, the mechanisms that contribute to p53-dependent apoptosis remain to be fully elucidated. In a comprehensive screen for p53 target genes, we have identified Cytoplasmic FMR Interacting Protein 2 (CYFIP2) as a p53-inducible gene. Here we show that the CYFIP2 promoter contains a p53-responsive element that confers p53 binding as well as transcriptional activation of a heterologous reporter. Inducible expression of CYFIP2 is sufficient for caspase activation and cellular apoptosis, reminiscent of p53 activation. Together, these results suggest that CYFIP2 is a direct p53 target gene that may be part of a redundant network of genes responsible for p53-dependent apoptosis. In addition, the sensitivity of CYFIP2 protein subcellular localization to Leptomycin-B, a CRM-1/Exportin inhibitor, suggests that the biological functions of CYFIP2 may extend from the cytoplasmic compartment into the nucleus of the cell.
Insights
The tumor suppressor p53 induces apoptosis through target genes. Researchers identified Cytoplasmic FMR Interacting Protein 2 (CYFIP2) as a direct p53 target gene involved in this process.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The tumor suppressor p53 plays a critical role in apoptosis, but its target genes and mechanisms are not fully understood.
- Identifying novel p53 target genes is crucial for elucidating p53-dependent apoptotic pathways.
Purpose of the Study:
- To identify novel p53 target genes involved in apoptosis.
- To investigate the role of Cytoplasmic FMR Interacting Protein 2 (CYFIP2) in p53-mediated apoptosis.
Main Methods:
- Comprehensive screening for p53 target genes.
- Analysis of the CYFIP2 promoter for p53-responsive elements.
- Reporter assays to confirm transcriptional activation.
- Inducible expression of CYFIP2 to assess apoptosis.
- Investigation of CYFIP2 subcellular localization using Leptomycin-B.
Main Results:
- Cytoplasmic FMR Interacting Protein 2 (CYFIP2) was identified as a p53-inducible gene.
- The CYFIP2 promoter contains a functional p53-responsive element, confirming direct p53 binding and transcriptional activation.
- Inducible CYFIP2 expression triggers caspase activation and apoptosis.
- CYFIP2's subcellular localization is sensitive to CRM-1/Exportin inhibition, suggesting nuclear-cytoplasmic shuttling.
Conclusions:
- CYFIP2 is a direct transcriptional target of p53.
- CYFIP2 is implicated as a mediator of p53-dependent apoptosis, potentially within a redundant gene network.
- CYFIP2's dynamic subcellular localization suggests its functions may involve both cytoplasmic and nuclear compartments.