Antiproliferative protein Tob directly regulates c-myc proto-oncogene expression through cytoplasmic polyadenylation element-binding protein CPEB

Oncogene. 2014 Jan 2;33(1):55-64. doi: 10.1038/onc.2012.548. Epub 2012 Nov 26.

Abstract

The regulation of mRNA deadenylation constitutes a pivotal mechanism of the post-transcriptional control of gene expression. Here we show that the antiproliferative protein Tob, a component of the Caf1-Ccr4 deadenylase complex, is involved in regulating the expression of the proto-oncogene c-myc. The c-myc mRNA contains cis elements (CPEs) in its 3'-untranslated region (3'-UTR), which are recognized by the cytoplasmic polyadenylation element-binding protein (CPEB). CPEB recruits Caf1 deadenylase through interaction with Tob to form a ternary complex, CPEB-Tob-Caf1, and negatively regulates the expression of c-myc by accelerating the deadenylation and decay of its mRNA. In quiescent cells, c-myc mRNA is destabilized by the trans-acting complex (CPEB-Tob-Caf1), while in cells stimulated by the serum, both Tob and Caf1 are released from CPEB, and c-Myc expression is induced early after stimulation by the stabilization of its mRNA as an 'immediate-early gene'. Collectively, these results indicate that Tob is a key factor in the regulation of c-myc gene expression, which is essential for cell growth. Thus, Tob appears to function in the control of cell growth at least, in part, by regulating the expression of c-myc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Base Sequence
  • Culture Media, Serum-Free
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Molecular Sequence Data
  • Polyadenylation
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stress, Physiological
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / physiology*
  • mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

  • 3' Untranslated Regions
  • CNOT8 protein, human
  • CPEB1 protein, human
  • Culture Media, Serum-Free
  • Intracellular Signaling Peptides and Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • TOB1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • mRNA Cleavage and Polyadenylation Factors