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Published on: April 25, 2018
Ribosomal proteins L5 and L11 co-operatively inactivate c-Myc via RNA-induced silencing complex
J-M Liao1, X Zhou1, A Gatignol2
1Department of Biochemistry and Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
Abstract:
Oncogene MYC is highly expressed in many human cancers and functions as a global regulator of ribosome biogenesis. Previously, we reported that ribosomal protein (RP) L11 binds to c-Myc and inhibits its transcriptional activity in response to ribosomal stress. Here, we show that RPL5, co-operatively with RPL11, guides the RNA-induced silencing complex (RISC) to c-Myc mRNA and mediates the degradation of the mRNA, consequently leading to inhibition of c-Myc activity. Knocking down of RPL5 induced c-Myc expression at both mRNA and protein levels, whereas overexpression of RPL5 suppressed c-Myc expression and activity. Immunoprecipitation revealed that RPL5 binds to 3'UTR of c-Myc mRNA and two subunits of RISC, TRBP (HIV-1 TAR RNA-binding protein) and Ago2, mediating the targeting of c-Myc mRNA by miRNAs. Interestingly, RPL5 and RPL11 co-resided on c-Myc mRNA and suppressed c-Myc expression co-operatively. These findings uncover a mechanism by which these two RPs can co-operatively suppress c-Myc expression, allowing a tightly controlled ribosome biogenesis in cells.
Insights
Ribosomal proteins RPL5 and RPL11 cooperatively suppress the oncogene MYC by guiding the RNA-induced silencing complex (RISC) to MYC mRNA, inhibiting cancer cell growth and controlling ribosome biogenesis.
Area of Science:
- Molecular Biology
- Cancer Biology
- Gene Regulation
Background:
- The oncogene MYC is frequently overexpressed in human cancers.
- MYC regulates ribosome biogenesis, a process critical for cell growth.
- Ribosomal protein L11 (RPL11) was previously shown to inhibit MYC activity under ribosomal stress.
Purpose of the Study:
- To investigate the role of ribosomal protein L5 (RPL5) in regulating MYC expression.
- To elucidate the mechanism by which RPL5 and RPL11 control MYC activity.
- To understand the implications for ribosome biogenesis and cancer.
Main Methods:
- Knockdown and overexpression of RPL5 in cells.
- Immunoprecipitation assays to detect protein-RNA interactions.
- Analysis of MYC mRNA and protein levels.
- Assessment of RNA-induced silencing complex (RISC) components.
Main Results:
- RPL5, together with RPL11, directs RISC to MYC mRNA, promoting its degradation.
- RPL5 binds to the 3'UTR of MYC mRNA and RISC subunits (TRBP, Ago2).
- Loss of RPL5 increases MYC expression, while RPL5 overexpression suppresses it.
Conclusions:
- RPL5 and RPL11 cooperatively suppress MYC expression through mRNA degradation mediated by RISC.
- This mechanism provides a novel pathway for controlling MYC levels and ribosome biogenesis.
- Targeting this pathway could offer therapeutic strategies for MYC-driven cancers.
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