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Human vtRNA1-1 Levels Modulate Signaling Pathways and Regulate Apoptosis in Human Cancer Cells
Lisamaria Bracher1,2, Iolanda Ferro1, Carlos Pulido-Quetglas2,3,4
1Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.
Abstract:
Regulatory non-protein coding RNAs perform a remarkable variety of complex biological functions. Previously, we demonstrated a role of the human non-coding vault RNA1-1 (vtRNA1-1) in inhibiting intrinsic and extrinsic apoptosis in several cancer cell lines. Yet on the molecular level, the function of the vtRNA1-1 is still not fully clear. Here, we created HeLa knock-out cell lines revealing that prolonged starvation triggers elevated levels of apoptosis in the absence of vtRNA1-1 but not in vtRNA1-3 knock-out cells. Next-generation deep sequencing of the mRNome identified the PI3K/Akt pathway and the ERK1/2 MAPK cascade, two prominent signaling axes, to be misregulated in the absence of vtRNA1-1 during starvation-mediated cell death conditions. Expression of vtRNA1-1 mutants identified a short stretch of 24 nucleotides of the vtRNA1-1 central domain as being essential for successful maintenance of apoptosis resistance. This study describes a cell signaling-dependent contribution of the human vtRNA1-1 to starvation-induced programmed cell death.
Insights
The human vault RNA1-1 (vtRNA1-1) protects against starvation-induced apoptosis by regulating key cell signaling pathways. Its absence leads to increased programmed cell death, highlighting its crucial role in cell survival.
Area of Science:
- Molecular Biology
- Cell Biology
- RNA Biology
Background:
- Non-coding RNAs (ncRNAs) regulate diverse biological functions.
- Human vault RNA1-1 (vtRNA1-1) was previously shown to inhibit apoptosis in cancer cells.
- The precise molecular mechanisms of vtRNA1-1 function remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular function of vtRNA1-1 in programmed cell death.
- To investigate the role of vtRNA1-1 in starvation-induced apoptosis.
- To identify the signaling pathways regulated by vtRNA1-1 during cell death.
Main Methods:
- Creation of HeLa knockout cell lines for vtRNA1-1 and vtRNA1-3.
- Induction of prolonged starvation to trigger apoptosis.
- Next-generation deep sequencing of the mRNome to analyze gene expression.
- Expression of vtRNA1-1 mutants to identify functional domains.
Main Results:
- Absence of vtRNA1-1, but not vtRNA1-3, resulted in elevated apoptosis during prolonged starvation.
- Deep sequencing revealed misregulation of the PI3K/Akt and ERK1/2 MAPK signaling pathways in vtRNA1-1 knockout cells.
- A 24-nucleotide central domain of vtRNA1-1 was identified as essential for apoptosis resistance.
Conclusions:
- Human vtRNA1-1 plays a critical role in resisting starvation-induced programmed cell death.
- vtRNA1-1 regulates apoptosis through modulation of the PI3K/Akt and ERK1/2 MAPK signaling pathways.
- The central domain of vtRNA1-1 is crucial for its anti-apoptotic function during starvation.
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