Involvement of the CCR4-NOT Deadenylase Complex in the Control of Cell Growth

  • Masahiro Morita
  • Kentaro Ito
  • Toru Suzuki
  • Tadashi Yamamoto
Conference paper

The Tob/BTG family comprises six proteins, Tob, Tob2, ANA, BTG1, BTG2/PC3/ TIS21, and PC3B, which share a common amino-terminal domain (1). All these proteins, when overexpressed, suppress growth of NIH3T3 cells (2). There is evidence that the Tob/BTG family of proteins is involved in regulation not only of cell growth but also of differentiation and development. For instance, BTG1 is thought to be involved in myogenesis induced by triiodothyronine (3). Analysis of tob-deficient mice revealed that Tob is involved in bone development (4). Although they lack DNA-binding domains, the Tob/BTG proteins are generally viewed as tran-scriptional cofactors. For example, Tob interacts with Smad in BMP2 signaling (4) and in T-cell anergy (5). BTG2 enhances Hoxb9-mediated transcription (6). Both Tob and BTG2 reduce cyclin D1 expression (7,8), possibly by recruiting histone deacetylase to the cyclin D1 promoter (9), contributing to G0/G1 arrest. On the other hand, Tob/Btg family proteins are also implicated in translational regulation by regulating the deadenylase activity or by interacting with the polyA binding proteins (10).

The CCR4-NOT complex is a large (>1 MDa) multi-subunit protein complex and is conserved from yeast to humans (11). The mammalian CCR4-NOT complex consists of 10 Cnot proteins: Cnot1-Cnot4, Ccr4a/Cnot6, Ccr4b/Cnot6L, Caf1/ Cnot7, Pop2/Cnot8, Caf40/Cnot9, and Caf130/Cnot10 (Table 1). Yeast CCR4-NOT has been considered to be a global transcription complex that regulates a variety of genes such as the nonfermentative gene either positively or negatively (11). Accumulating evidence also shows that the mammalian Cnot proteins interact with proteins in the transcription machinery. For example, Cnot1 and Cnot7 are reported to interact with estrogen receptor-α (12,13). Cnot7 is also shown to interact with retinoid X receptor-β (14). Another report showed that Cnot9 is associated with retinoic acid receptor-α (15). Therefore, the mammalian CCR4-NOT complex appears to be involved in various transcription events controlled by the nuclear


Prog Nucleic Acid mRNA Deadenylation Deadenylase Activity polyA Binding Protein Estrogen Receptor Alpha Signaling 
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  1. 1.
    Tirone F (2001) The gene PC3 (TIS21/BTG2), prototype member of the PC3/BTG TOB family: regulator in control of cell growth, differentiation, and DNA repair? J Cell Physiol 187:155–165PubMedCrossRefGoogle Scholar
  2. 2.
    Jia S, Meng A (2007) Tob genes in development and homeostasis. Dev Dyn 236:913–921PubMedCrossRefGoogle Scholar
  3. 3.
    Rodier A et al. (1999) BTG1: a triiodothyronine target involved in the myogenic influence of the hormone. Exp Cell Res 249:337–348PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshida Y et al. (2000) Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103:1085–1097PubMedCrossRefGoogle Scholar
  5. 5.
    Tzachanis D et al. (2001) Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol 2:1174–1182PubMedCrossRefGoogle Scholar
  6. 6.
    Prevot D et al. (2000) The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. J Biol Chem 275:147–153PubMedCrossRefGoogle Scholar
  7. 7.
    Guardavaccaro D et al. (2000) Arrest of G(1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription. Mol Cell Biol 20:1797–1815PubMedCrossRefGoogle Scholar
  8. 8.
    Suzuki T et al. (2002) Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes Dev 16:1356–1370PubMedCrossRefGoogle Scholar
  9. 9.
    Yoshida Y et al. (2003) Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev 17:1201–1206PubMedCrossRefGoogle Scholar
  10. 10.
    Okochi K et al. (2005) Interaction of anti-proliferative protein Tob with poly(A)-binding protein and inducible poly(A)-binding protein: implication of Tob in translational control. Genes Cells 10:151–163PubMedCrossRefGoogle Scholar
  11. 11.
    Collart MA, Timmers HT (2004) The eukaryotic Ccr4-not complex: a regulatory platform integrating mRNA metabolism with cellular signaling pathways? Prog Nucleic Acid Res Mol Biol 77:289–322PubMedCrossRefGoogle Scholar
  12. 12.
    Winkler GS et al. (2006) Human Ccr4-Not complex is a ligand-dependent repressor of nuclear receptor-mediated transcription. EMBO J 25:3089–3099PubMedCrossRefGoogle Scholar
  13. 13.
    Prevot D et al. (2001) Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: involvement in estrogen receptor alpha signaling pathway. J Biol Chem 276:9640–9648PubMedCrossRefGoogle Scholar
  14. 14.
    Nakamura T et al. (2004) Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor β. Nat Genet 36:528–533PubMedCrossRefGoogle Scholar
  15. 15.
    Hiroi N et al. (2002) Mammalian Rcd1 is a novel transcriptional cofactor that mediates retinoic acid-induced cell differentiation. EMBO J 21:5235–5244PubMedCrossRefGoogle Scholar
  16. 16.
    Miyasaka et al. (2008) Interaction of antiproliferative protein Tob with the CCR4-NOT dead-enylase complex. Cancer Sci 99:755–761PubMedCrossRefGoogle Scholar
  17. 17.
    Meyer S et al. (2004) Messenger RNA turnover in eukaryotes: pathways and enzymes. Crit Rev Biochem Mol Biol 39:197–216PubMedCrossRefGoogle Scholar
  18. 18.
    Garneau NL et al. (2007) The highways and byways of mRNA decay. Nat Rev Mol Cell Biol 8:113–126PubMedCrossRefGoogle Scholar
  19. 19.
    Denis CL, Chen J (2003) The CCR4-NOT complex plays diverse roles in mRNA metabolism. Prog Nucleic Acids Res Mol Biol 73:221–250CrossRefGoogle Scholar
  20. 20.
    Ikematsu N et al. (1999) Tob2, a novel anti-proliferative Tob/BTG1 family member, associates with a component of the CCR4 transcriptional regulatory complex capable of binding cyclin-dependent kinases. Oncogene 18:7432–7441PubMedCrossRefGoogle Scholar
  21. 21.
    Morita M et al. (2007) Depletion of mammalian CCR4b deadenylasetriggers increment of the p27 Kip1 mRNA level and impaires cell growth. Mol Cell Biol 27:4980–4990PubMedCrossRefGoogle Scholar
  22. 22.
    Chen CYA, and Shyu AB (1995) AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci 20:465–470PubMedCrossRefGoogle Scholar
  23. 23.
    Behm-Ansmant I et al. (2006) mRNA degradation by microRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev 20:1885–1898CrossRefGoogle Scholar
  24. 24.
    Ding L, Han M (2007) GW182 family proteins are crucial for microRNA-mediated gene silencing. Trends Cell Biol 17:411–416PubMedCrossRefGoogle Scholar
  25. 25.
    Ezzeddine N et al. (2007) Human TOB, an antiproliferative transcription factor, is a poly(A)-binding protein-dependent positive regulator of cytoplasmic mRNA deadenylation. Mol Cell Biol 27:7791–7801PubMedCrossRefGoogle Scholar
  26. 26.
    Funakoshi Y et al. (2007) Mechanism of mRNA deadenylation: evidence for a molecular interplay between translation termination factor eRF3 and mRNA deadenylases. Genes Dev 23:3135–3148CrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Masahiro Morita
    • 1
  • Kentaro Ito
    • 1
  • Toru Suzuki
    • 1
  • Tadashi Yamamoto
    • 1
  1. 1.Division of Oncology, The Institute of Medical ScienceThe University of TokyoMinatok-ku

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