PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia

Oncogene. 2005 Feb 3;24(6):992-1000. doi: 10.1038/sj.onc.1208302.

Abstract

Protein kinase (PK)C theta is a critical regulator of mature T-cell activation and proliferation, being implicated in TCR-triggered nuclear factor (NF)-kappa B activation and providing important survival signals to leukemic T cells. We previously showed that overexpression of pT alpha/pre-TCR and constitutive activation of NF-kappa B characterize the T-cell leukemia/lymphoma developing in Notch3-IC transgenic mice. We report here that PKC theta is a downstream target of Notch3 signaling and that its activation and membrane translocation require a functional pre-TCR in order to trigger NF-kappa B activation in thymocytes and lymphoma cells of transgenic mice. Furthermore, deletion of PKC theta in Notch3-IC transgenic mice reduces the incidence of leukemia, correlating with decreased NF-kappa B activation. This paper therefore suggests that PKC theta mediates the activation of NF-kappa B by pre-TCR in immature thymocytes and contributes to the development of Notch3-dependent T-cell lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane
  • Isoenzymes / genetics*
  • Isoenzymes / pharmacokinetics
  • Isoenzymes / pharmacology*
  • Leukemia, T-Cell / genetics*
  • Leukemia, T-Cell / physiopathology*
  • Lymphoma, T-Cell
  • Membrane Glycoproteins
  • Mice
  • Mice, Transgenic
  • NF-kappa B / genetics
  • NF-kappa B / pharmacology
  • Protein Kinase C / genetics*
  • Protein Kinase C / pharmacokinetics
  • Protein Kinase C / pharmacology*
  • Protein Kinase C-theta
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / pharmacology*
  • Receptor, Notch3
  • Receptor, Notch4
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Cell Surface / genetics*
  • Receptors, Notch
  • Signal Transduction
  • Thymus Gland / cytology
  • Zinc Fingers

Substances

  • Isoenzymes
  • Membrane Glycoproteins
  • NF-kappa B
  • Notch3 protein, mouse
  • Proto-Oncogene Proteins
  • Receptor, Notch3
  • Receptor, Notch4
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Cell Surface
  • Receptors, Notch
  • pre-T cell receptor alpha
  • Notch4 protein, mouse
  • PRKCQ protein, human
  • Protein Kinase C
  • Protein Kinase C-theta