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Ribosomal protein S14 negatively regulates c-Myc activity.

Abstract
The ribosomal gene RPS14 is associated with the cancer-prone 5q-syndrome, which is caused by an interstitial deletion of the long arm of human chromosome 5. Previously, we found that ribosomal protein S14 (RPS14) binds to and inactivates MDM2, consequently leading to p53-dependent cell-cycle arrest and growth inhibition. However, it remains elusive whether RPS14 regulates cell proliferation in a p53-independent manner. Here, we show that RPS14 interacts with the Myc homology box II (MBII) and the C-terminal basic helix-loop-helix leucine zipper (bHLH-LZ) domains of the oncoprotein c-Myc. Further, RPS14 inhibited c-Myc transcriptional activity by preventing the recruitment of c-Myc and its cofactor, TRRAP, to the target gene promoters, as thus suppressing c-Myc-induced cell proliferation. Also, siRNA-mediated RPS14 depletion elevated c-Myc transcriptional activity determined by its target gene, Nucleolin, expression. Interestingly, RPS14 depletion also resulted in the induction of c-Myc mRNA and subsequent protein levels. Consistent with this, RPS14 promoted c-Myc mRNA turnover through an Argonaute 2 (Ago2)- and microRNA-mediated pathway. Taken together, our study demonstrates that RPS14 negates c-Myc functions by directly inhibiting its transcriptional activity and mediating its mRNA degradation via miRNA.
AuthorsXiang Zhou, Qian Hao, Jun-Ming Liao, Peng Liao, Hua Lu
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 30 Pg. 21793-801 (Jul 26 2013) ISSN: 1083-351X [Electronic] United States
PMID23775087 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • AGO2 protein, human
  • Adaptor Proteins, Signal Transducing
  • Argonaute Proteins
  • MicroRNAs
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • RNA-Binding Proteins
  • RPS14 protein, human
  • Ribosomal Proteins
  • nucleolin
  • transformation-transcription domain-associated protein
Topics
  • Adaptor Proteins, Signal Transducing (genetics, metabolism)
  • Argonaute Proteins (genetics, metabolism)
  • Binding Sites (genetics)
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Immunoblotting
  • MicroRNAs (genetics, metabolism)
  • Nuclear Proteins (genetics, metabolism)
  • Phosphoproteins (genetics, metabolism)
  • Promoter Regions, Genetic (genetics)
  • Protein Binding
  • Proto-Oncogene Proteins c-myc (genetics, metabolism)
  • RNA Interference
  • RNA, Messenger (genetics, metabolism)
  • RNA-Binding Proteins (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Proteins (genetics, metabolism)
  • Signal Transduction (genetics)
  • Transcriptional Activation

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