14-3-3Tau regulates ubiquitin-independent proteasomal degradation of p21, a novel mechanism of p21 downregulation in breast cancer

Mol Cell Biol. 2010 Mar;30(6):1508-27. doi: 10.1128/MCB.01335-09. Epub 2010 Jan 19.


14-3-3 proteins regulate many cellular functions, including proliferation. However, the detailed mechanisms by which they control the cell cycle remain to be fully elucidated. We report that one of the 14-3-3 isoforms, 14-3-3tau, is required for the G(1)/S transition through its role in ubiquitin-independent proteasomal degradation of p21. 14-3-3tau binds to p21, MDM2, and the C8 subunit of the 20S proteasome in G(1) phase and facilitates proteasomal targeting of p21. This function of 14-3-3tau may be deregulated in cancer. The overexpression of 14-3-3tau is frequently found in primary human breast cancer and correlates with lower levels of p21 and shorter patient survival. Tenascin-C, an extracellular matrix protein involved in tumor initiation and progression and a known 14-3-3tau inducer, decreases p21 and abrogates adriamycin-induced G(1)/S arrest. It has been known that p21 is required for a proper tamoxifen response in breast cancer. We show that the overexpression of 14-3-3tau inhibits tamoxifen-induced p21 induction and growth arrest in MCF7 cells. Together, the findings of our studies strongly suggest a novel oncogenic role of 14-3-3tau by downregulating p21 in breast cancer. Therefore, 14-3-3tau may be a potential therapeutic target in breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Down-Regulation* / drug effects
  • Female
  • G1 Phase / drug effects
  • Humans
  • Mice
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding / drug effects
  • Protein Processing, Post-Translational* / drug effects
  • Protein Stability / drug effects
  • Protein Subunits / metabolism
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Signal Transduction / drug effects
  • Survival Analysis
  • Tamoxifen / pharmacology
  • Tenascin / metabolism
  • Ubiquitin / metabolism


  • 14-3-3 Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Protein Subunits
  • Tenascin
  • Ubiquitin
  • Tamoxifen
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Proteasome Endopeptidase Complex