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Updated: Aug 25, 2026
Establishing Cell Lines Overexpressing DR3 to Assess the Apoptotic Response to Anti-mitotic Therapeutics
Published on: January 11, 2019
A novel apoptotic pathway induced by the drs tumor suppressor gene
Yukihiro Tambe1, Takahiro Isono, Seiki Haraguchi
1Department of Microbiology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Abstract:
The drs gene was originally isolated as a suppressor against v-src transformation. Expression of drs mRNA was markedly downregulated in a variety of human cancer cell lines and tissues, suggesting that the drs gene acts as a tumor suppressor. In this study, we found that ectopic expression of the Drs protein induced apoptosis in human cancer cell lines. Analyses using deletion mutants of drs revealed that both the C-terminal region and the three consensus repeats in the N-terminal region are essential for the induction of apoptosis. Caspase-12, -9, and -3 were sequentially activated by drs, and specific inhibitors of caspase-3 and -9 suppressed drs-induced apoptosis. The release of cytochrome c from the mitochondria into the cytoplasm was not observed in apoptosis by drs, suggesting that the mitochondrial pathway does not mediate drs-induced apoptosis. Furthermore, we found that the Drs protein can interact with ASY/Nogo-B/RTN-x(S), an apoptosis-inducing protein localized in the endoplasmic reticulum, and that coexpression of these genes increased the efficiency of apoptosis. These results indicated that Drs induces apoptosis by a novel pathway mediated by ASY/Nogo-B/RTN-x(S), caspase-12, -9, and -3.
Insights
The Drs protein suppresses tumors by inducing programmed cell death (apoptosis) in cancer cells. It activates caspases via a novel endoplasmic reticulum pathway, distinct from the mitochondrial route.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Biology
Background:
- The drs gene was identified as a suppressor of v-src transformation.
- Drs mRNA downregulation in human cancers suggests a tumor suppressor role.
- The Drs protein's function in apoptosis induction requires elucidation.
Purpose of the Study:
- To investigate the role of the Drs protein in inducing apoptosis in human cancer cell lines.
- To identify the molecular mechanisms and pathways involved in Drs-mediated apoptosis.
- To determine the specific domains of Drs essential for apoptosis induction.
Main Methods:
- Ectopic expression of the Drs protein and its deletion mutants in human cancer cell lines.
- Analysis of caspase activation (caspase-12, -9, -3) and inhibition studies.
- Assessment of cytochrome c release from mitochondria.
- Investigation of protein-protein interactions between Drs and ASY/Nogo-B/RTN-x(S).
Main Results:
- Ectopic Drs expression induced apoptosis in cancer cells.
- Both N-terminal and C-terminal regions of Drs are crucial for apoptosis induction.
- Drs sequentially activated caspase-12, -9, and -3, independent of mitochondrial cytochrome c release.
- Drs interacts with ASY/Nogo-B/RTN-x(S), enhancing apoptosis.
Conclusions:
- Drs induces apoptosis through a novel pathway involving the endoplasmic reticulum protein ASY/Nogo-B/RTN-x(S).
- This pathway sequentially activates caspase-12, -9, and -3, bypassing the mitochondrial route.
- Drs functions as a tumor suppressor by initiating a distinct apoptotic cascade.
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