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Published on: May 26, 2017
Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling
Zain Paroo1, Xuecheng Ye, She Chen
1Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Abstract:
MicroRNAs (miRNAs) govern an expanding number of biological and disease processes. Understanding the mechanisms by which the miRNA pathway is regulated, therefore, represents an important area of investigation. We determined that the human miRNA-generating complex is comprised of Dicer and phospho-TRBP isoforms. Phosphorylation of TRBP is mediated by the mitogen-activated protein kinase (MAPK) Erk. Expression of phospho-mimic TRBP and TRBP phosphorylation enhanced miRNA production by increasing stability of the miRNA-generating complex. Mitogenic signaling in response to serum and the tumor promoter PMA was dependent on TRBP phosphorylation. These effects were accompanied by a coordinated increase in levels of growth-promoting miRNA and reduced expression of let-7 tumor suppressor miRNA. Conversely, pharmacological inhibition of MAPK/Erk resulted in an anti-growth miRNA profile. Taken together, these studies indicate that the MAPK/Erk pathway regulates the miRNA machinery and suggest a general principle, wherein signaling systems target the miRNA pathway to achieve biological responses.
Insights
The MAPK/Erk pathway regulates microRNA (miRNA) production by phosphorylating TRBP, enhancing miRNA biogenesis. This signaling controls cell growth and tumor suppressor miRNA levels.
Area of Science:
- Molecular Biology
- Cell Signaling
Background:
- MicroRNAs (miRNAs) are crucial regulators of biological and disease processes.
- Understanding miRNA pathway regulation is vital for investigating cellular mechanisms.
Purpose of the Study:
- To elucidate the regulatory mechanisms of the human miRNA-generating complex.
- To identify the role of mitogen-activated protein kinase (MAPK) Erk in miRNA production.
Main Methods:
- Investigated the composition of the miRNA-generating complex using Dicer and phospho-TRBP isoforms.
- Examined the effect of TRBP phosphorylation by MAPK/Erk on miRNA production.
- Assessed the impact of MAPK/Erk signaling on miRNA profiles in response to serum and PMA.
Main Results:
- The miRNA-generating complex comprises Dicer and phospho-TRBP.
- TRBP phosphorylation by MAPK/Erk enhances miRNA production by stabilizing the complex.
- Mitogenic signaling and tumor promotion involve TRBP phosphorylation, altering growth-promoting and tumor suppressor miRNA levels.
Conclusions:
- The MAPK/Erk pathway directly regulates the miRNA machinery.
- Signaling pathways target the miRNA pathway to mediate biological responses.
- TRBP phosphorylation is a key mechanism linking MAPK/Erk signaling to miRNA biogenesis.
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