PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia.
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.
Felli
Maria Pia
MP
Department of Experimental Medicine and Pathology, University La Sapienza, 00161 Roma, Italy.
Vacca
Alessandra
A
Calce
Angelica
A
Bellavia
Diana
D
Campese
Antonio F
AF
Grillo
Rita
R
Di Giovine
Monica
M
Checquolo
Saula
S
Talora
Claudio
C
Palermo
Rocco
R
Di Mario
Giuseppina
G
Frati
Luigi
L
Gulino
Alberto
A
Screpanti
Isabella
I
D000818:Animals; D002462:Cell Membrane; D007527:Isoenzymes / Q000235:genetics* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000503:physiopathology*; D016399:Lymphoma, T-Cell; D008562:Membrane Glycoproteins; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000074121:Protein Kinase C-theta; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000494:pharmacology*; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011956:Receptors, Cell Surface / Q000235:genetics*; D051880:Receptors, Notch; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology; D016335:Zinc Fingers
D007527:Isoenzymes; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C499373:Notch3 protein, mouse; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; C090377:pre-T cell receptor alpha; C073572:Notch4 protein, mouse; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta