TY - JOUR
AU - Screpanti, Isabella
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 overexpress 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.
TI - Notch3 and pre‐TCR interaction unveils distinct NF‐κB pathways in T‐cell development and leukemia
JF - The EMBO Journal
DO - 10.1038/sj.emboj.7600996
DA - 2006-03-08
UR - https://www.deepdyve.com/lp/springer-journals/notch3-and-pre-tcr-interaction-unveils-distinct-nf-b-pathways-in-t-JACLOeTH04
SP - 1000
EP - 1008
VL - 25
IS - 5
DP - DeepDyve
ER -