Inhibition of c-Myc activity by ribosomal protein L11

EMBO J. 2007 Jul 25;26(14):3332-45. doi: 10.1038/sj.emboj.7601776. Epub 2007 Jun 28.

Abstract

The c-Myc oncoprotein promotes cell growth by enhancing ribosomal biogenesis through upregulation of RNA polymerases I-, II-, and III-dependent transcription. Overexpression of c-Myc and aberrant ribosomal biogenesis leads to deregulated cell growth and tumorigenesis. Hence, c-Myc activity and ribosomal biogenesis must be regulated in cells. Here, we show that ribosomal protein L11, a component of the large subunit of the ribosome, controls c-Myc function through a negative feedback mechanism. L11 is transcriptionally induced by c-Myc, and overexpression of L11 inhibits c-Myc-induced transcription and cell proliferation. Conversely, reduction of endogenous L11 by siRNA increases these c-Myc activities. Mechanistically, L11 binds to the Myc box II (MB II), inhibits the recruitment of the coactivator TRRAP, and reduces histone H4 acetylation at c-Myc target gene promoters. In response to serum stimulation or serum starvation, L11 and TRRAP display inverse promoter-binding profiles. In addition, L11 regulates c-Myc levels. These results identify L11 as a feedback inhibitor of c-Myc and suggest a novel role for L11 in regulating c-Myc-enhanced ribosomal biogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • Cell Proliferation
  • Gene Expression
  • Histones / metabolism
  • Humans
  • Mice
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / chemistry
  • Proto-Oncogene Proteins c-myc / genetics
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Ribosomal Proteins / chemistry
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism*
  • S Phase
  • Serum
  • Transcription, Genetic
  • Transcriptional Activation / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Histones
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Ribosomal Proteins
  • nucleolin
  • ribosomal protein L11
  • ribosomal protein L29
  • transformation-transcription domain-associated protein