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Ribosomal protein S6 is highly expressed in non-Hodgkin lymphoma and associates with mRNA containing a 5′ terminal oligopyrimidine tract

Oncogene volume 30, pages 1531–1541 (2011)Cite this article

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Abstract

The molecular mechanism(s) linking tumorigenesis and morphological alterations in the nucleolus are presently coming into focus. The nucleolus is the cellular organelle in which the formation of ribosomal subunits occurs. Ribosomal biogenesis occurs through the transcription of ribosomal RNA (rRNA), rRNA processing and production of ribosomal proteins. An error in any of these processes may lead to deregulated cellular translation, evident in multiple cancers and ‘ribosomopathies’. Deregulated protein synthesis may be achieved through the overexpression of ribosomal proteins as seen in primary leukemic blasts with elevated levels of ribosomal proteins S11 and S14. In this study, we demonstrate that ribosomal protein S6 (RPS6) is highly expressed in primary diffuse large B-cell lymphoma (DLBCL) samples. Genetic modulation of RPS6 protein levels with specifically targeted short hairpin RNA (shRNA) lentiviruses led to a decrease in the actively proliferating population of cells compared with control shRNA. Low-dose rapamycin treatments have been shown to affect the translation of 5′ terminal oligopyrimidine (5′ TOP) tract mRNA, which encodes the translational machinery, implicating RPS6 in 5′ TOP translation. Recently, it was shown that disruption of 40S ribosomal biogenesis through specific small inhibitory RNA knockdown of RPS6 defined RPS6 as a critical regulator of 5′ TOP translation. For the first time, we show that RPS6 associates with multiple mRNAs containing a 5′ TOP tract. These findings expand our understanding of the mechanism(s) involved in ribosomal biogenesis and deregulated protein synthesis in DLBCL.

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Acknowledgements

The WT-RPS16-hGH and Cm5-RPS16-hGH constructs that contain the coding region of hGH fused to the first 29 nucleotides of the RPS16 5′ untranslated region (WT-RPS16-hGH) or to the mutant in which five of the eight pyrimidines within the 5′ TOP have been mutated to purines (Cm5) were kindly provided by the laboratories of Dr Oded Meyuhas and Dr George Thomas, This work was funded in part by a Merit Review Award from the Department of Veterans Affairs (RBG) and R01AA017972 from the National Institutes of Health (RBG).

Contributions: PRH performed the research, analyzed the data and wrote the paper. KMM performed the research, analyzed the data and wrote the paper. EMB, SSM and XFZ analyzed the data. SC performed the research. BD performed the research and analyzed the data. RBG conceived of and designed the research, analyzed the data and wrote the paper.

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Authors and Affiliations

  1. Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    P R Hagner, K Mazan-Mamczarz, B Dai, E M Balzer, S Corl, S S Martin, X F Zhao & R B Gartenhaus

  2. Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    P R Hagner

  3. Veterans Administration Medical Center, Baltimore, MD, USA

    R B Gartenhaus

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  1. P R Hagner
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Correspondence to R B Gartenhaus.

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Hagner, P., Mazan-Mamczarz, K., Dai, B. et al. Ribosomal protein S6 is highly expressed in non-Hodgkin lymphoma and associates with mRNA containing a 5′ terminal oligopyrimidine tract. Oncogene 30, 1531–1541 (2011). https://doi.org/10.1038/onc.2010.533

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