Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma.
Notch and basic helix-loop-helix E2A pathways specify cell fate and regulate neoplastic transformation in a variety of cell types. Whereas Notch enhances tumorigenesis, E2A suppresses it. However, whether and how Notch and E2A interact functionally in an integrative mechanism for regulating neoplastic transformation remains to be understood. It has been shown that Notch3-induced T-cell leukaemia is abrogated by the inactivation of pTalpha/pre-T-cell antigen receptor (pre-TCR). We report here that Notch3-induced transcriptional activation of pTalpha/pre-TCR is responsible for the downregulation of E2A DNA binding and transcriptional activity. Further, the E2A messenger RNA and protein levels remain unaltered but the E2A inhibitor Id1 expression is augmented in thymocytes and T lymphoma cells derived from Notch3 transgenic mice. The increase in Id1 expression is achieved by pre-TCR-induced extracellular-signalling-regulated kinase 1/2. These observations support a model in which the upregulation of pre-TCR signalling seems to be the prerequi-site for Notch3-induced inhibition of E2A, thus leading to the development of lymphoma in Notch3 transgenic mice.
Talora
Claudio
C
Laboratory of Molecular Pathology, Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy.
Campese
Antonio F
AF
Bellavia
Diana
D
Pascucci
Monica
M
Checquolo
Saula
S
Groppioni
Manuela
M
Frati
Luigi
L
von Boehmer
Harald
H
Gulino
Alberto
A
Screpanti
Isabella
I
D000818:Animals; D015536:Down-Regulation; D018257:Helix-Loop-Helix Motifs; D051798:Inhibitor of Differentiation Protein 1; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*
C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; C499373:Notch3 protein, mouse; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D012097:Repressor Proteins; D014157:Transcription Factors; C073572:Notch4 protein, mouse; D020928:Mitogen-Activated Protein Kinases