HES1 opposes a PTEN-dependent check on survival, differentiation, and proliferation of TCRβ-selected mouse thymocytes

Blood. 2012 Aug 16;120(7):1439-48. doi: 10.1182/blood-2011-12-395319. Epub 2012 May 30.


The developmental progression of immature thymocytes requires cooperative input from several pathways, with Notch signals playing an indispensable role at the T-cell receptor (TCR)-β selection checkpoint. Notch signals affect the activation of the PI3K/Akt pathway, which is required for pTα/TCRβ (pre-TCR)-induced survival, differentiation, and proliferation of developing αβ-lineage thymocytes. However, the molecular players responsible for the interaction between the Notch and PI3K pathways at this critical developmental stage are unknown. Here, we show that Notch induction of Hes1 is necessary to repress the PI3K/Akt pathway inhibitor, PTEN (phosphatase and tensin homolog), which in turn facilitates pre-TCR-induced differentiation. In support of this mechanism, deletion or down-regulation of Pten overcomes the Notch signaling requirement for survival and differentiation during β-selection. In addition, c-Myc is a critical target of Notch at this stage, as c-Myc expression overcomes the Notch signaling requirement for proliferation during β-selection. Collectively, our results point to HES1, via repression of PTEN, and c-Myc as critical mediators of Notch function at the β-selection checkpoint.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation* / genetics
  • Cell Differentiation* / immunology
  • Cell Lineage / immunology
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Gene Deletion
  • Gene Knockdown Techniques
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / metabolism*
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • Mice
  • PTEN Phosphohydrolase / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Small Interfering / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Receptors, CXCR4 / metabolism
  • Receptors, Notch / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Thymocytes / cytology*
  • Thymocytes / enzymology*
  • Thymocytes / immunology
  • Transcription Factor HES-1
  • Transcription, Genetic
  • Up-Regulation / genetics
  • Up-Regulation / immunology


  • Basic Helix-Loop-Helix Transcription Factors
  • CXCR4 protein, mouse
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Interleukin-7 Receptor alpha Subunit
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, CXCR4
  • Receptors, Notch
  • Transcription Factor HES-1
  • PTEN Phosphohydrolase
  • Pten protein, mouse