Abstract
Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. Notch3-transgenic premalignant thymocytes and T lymphoma cells over-express pTα/pre-TCR and display constitutive activation of NF-κB, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-κB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-κB via IKKβ/IKKα/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-α genes. In contrast, upon pTα deletion, Notch3 binds IKKα and maintains NF-κB activation through an alternative pathway, depending on an NIK-independent IKKα homodimer activity. The consequent NF-κB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-α genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-κB activity, leading to differential NF-κB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis.
| Original language | English |
|---|---|
| Pages (from-to) | 1000-1008 |
| Number of pages | 9 |
| Journal | EMBO Journal |
| Volume | 25 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Mar 8 2006 |
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Keywords
- IKKα
- NF-κB pathways
- Notch3
- Pre-TCR
ASJC Scopus subject areas
- Genetics
- Cell Biology
Cite this
Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia. / Vacca, Alessandra; Felli, Maria Pia; Palermo, Rocco; Di Mario, Giuseppina; Calce, Angelica; Di Giovine, Monica; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella.
In: EMBO Journal, Vol. 25, No. 5, 08.03.2006, p. 1000-1008.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia
AU - Vacca, Alessandra
AU - Felli, Maria Pia
AU - Palermo, Rocco
AU - Di Mario, Giuseppina
AU - Calce, Angelica
AU - Di Giovine, Monica
AU - Frati, Luigi
AU - Gulino, Alberto
AU - Screpanti, Isabella
PY - 2006/3/8
Y1 - 2006/3/8
N2 - Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. Notch3-transgenic premalignant thymocytes and T lymphoma cells over-express pTα/pre-TCR and display constitutive activation of NF-κB, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-κB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-κB via IKKβ/IKKα/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-α genes. In contrast, upon pTα deletion, Notch3 binds IKKα and maintains NF-κB activation through an alternative pathway, depending on an NIK-independent IKKα homodimer activity. The consequent NF-κB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-α genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-κB activity, leading to differential NF-κB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis.
AB - Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. Notch3-transgenic premalignant thymocytes and T lymphoma cells over-express pTα/pre-TCR and display constitutive activation of NF-κB, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-κB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-κB via IKKβ/IKKα/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-α genes. In contrast, upon pTα deletion, Notch3 binds IKKα and maintains NF-κB activation through an alternative pathway, depending on an NIK-independent IKKα homodimer activity. The consequent NF-κB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-α genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-κB activity, leading to differential NF-κB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis.
KW - IKKα
KW - NF-κB pathways
KW - Notch3
KW - Pre-TCR
UR - http://www.scopus.com/inward/record.url?scp=33644864057&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644864057&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7600996
DO - 10.1038/sj.emboj.7600996
M3 - Article
C2 - 16498412
AN - SCOPUS:33644864057
VL - 25
SP - 1000
EP - 1008
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 5
ER -