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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Impairing the microRNA biogenesis pathway induces proteome modifications characterized by size bias and enrichment in
Delphine Peric1, Jean Labarre, François Chevalier
1Commissariat à l'Energie Atomique, Laboratoire de Génétique de la Radiosensibilité, Fontenay aux Roses, France.
Abstract:
Perturbation of individual microRNAs, or of the microRNA pathway, plays a role in carcinogenesis. In certain cancer cells, inhibition of the microRNA biogenesis pathway leads to a growth arrest state (CoGAM for Colony Growth Arrest induced by Microprocessor inhibition), which can be rescued by re-expression of individual microRNAs such as miR-20a. We now report that inhibition of the microRNA biogenesis pathway induced proteome changes characterized by a size bias in differentially expressed proteins, with induction of small proteins and inhibition of large ones. This size bias was observed in cells undergoing CoGAM, as well as in CoGAM-resistant cells, and in CoGAM-sensitive cells rescued by miR-20a. In this case, GO analysis of induced proteins identified by mass spectrometry revealed a significant enrichment in proteins involved in resistance to oxidative stress. In addition, H(2) O(2) treatment of Saccharomyces cerevisiae or mammalian cells led to similarly size-biased proteome modifications. Our results point to size bias as a relevant readout of proteome modifications, in particular in conditions of stress such as inhibition of the microRNA biogenesis pathway or oxidative stress. They also suggest research avenues to study the role of the microRNA pathway in proteostasis.
Insights
Inhibition of microRNA biogenesis causes cancer cell growth arrest and alters protein expression, favoring smaller proteins. This size bias in proteome changes also occurs during oxidative stress, suggesting a role for microRNAs in proteostasis.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- MicroRNA (miRNA) pathway perturbation is implicated in cancer development.
- Inhibition of miRNA biogenesis can induce a cell growth arrest state (CoGAM), which is reversible by miRNA re-expression.
Purpose of the Study:
- To investigate proteome modifications induced by miRNA biogenesis inhibition.
- To explore the relationship between miRNA pathway, stress responses, and protein size bias.
Main Methods:
- Mass spectrometry-based proteomics to analyze protein expression changes.
- Gene Ontology (GO) analysis to identify enriched protein functions.
- Experimental induction of oxidative stress using H(2)O(2) in yeast and mammalian cells.
Main Results:
- miRNA biogenesis inhibition leads to a proteome size bias, with increased small proteins and decreased large proteins.
- This size bias is observed in CoGAM-sensitive, CoGAM-resistant, and rescued cells.
- Proteins induced during CoGAM are enriched in pathways related to oxidative stress resistance.
- Oxidative stress independently induces similar size-biased proteome modifications.
Conclusions:
- Proteome size bias is a significant indicator of cellular stress, including miRNA pathway disruption and oxidative stress.
- The miRNA pathway may play a crucial role in maintaining proteostasis under stress conditions.
- Further research into miRNA's role in proteostasis is warranted.
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