Cross talk among Notch3, pre-TCR, and Tal1 in T-cell development and leukemogenesis.
Integrated pathways are believed to determine hematopoietic cell fate and/or neoplastic transformation. Notch signaling has been shown to regulate T-cell differentiation and leukemogenesis. However, specific target genes and molecular partners are not fully elucidated. We show that Notch3 activation sustains aberrant SCL/Tal1 overexpression and phosphorylation in mature thymocytes. Furthermore, we define the role of SCL/Tal1 as a component of an activator complex, including phosphorylated Tal1 and Sp1, that specifically enhances cyclin D1 expression and demonstrate that Tal1/Sp1 specifically co-occupy the D1 promoter in vivo, only in the presence of pre-T-cell receptor (TCR). We therefore conclude not only that cyclin D1 is a target of the Tal1/Sp1 complex, but also that Notch3-dependent activation of pre-TCR/ERK signaling regulates SCL/Tal1 function.
Talora
Claudio
C
Dipartimento di Medicina Sperimentale e Patologia, University La Sapienza, Viale Regina Elena 32400161 Roma, Italy.
Cialfi
Samantha
S
Oliviero
Christian
C
Palermo
Rocco
R
Pascucci
Monica
M
Frati
Luigi
L
Vacca
Alessandra
A
Gulino
Alberto
A
Screpanti
Isabella
I
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000071656:Receptor, Notch3; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C499373:Notch3 protein, mouse; C489366:Tal1 protein, mouse