Notch activation is an early and critical event during T-Cell leukemogenesis in Ikaros-deficient mice.
The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (Ik(L/L)) in the Ikaros gene all develop thymic lymphomas. Ik(L/L) tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young Ik(L/L) mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this factor.
Dumortier
Alexis
A
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP, BP 10142, 67404 Illkirch, CU Strasbourg, France.
Jeannet
Robin
R
Kirstetter
Peggy
P
Kleinmann
Eva
E
Sellars
MacLean
M
dos Santos
Nuno R
NR
Thibault
Christelle
C
Barths
Jochen
J
Ghysdael
Jacques
J
Punt
Jennifer A
JA
Kastner
Philippe
P
Chan
Susan
S
D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D049109:Cell Proliferation; D018398:Homeodomain Proteins / Q000235:genetics*; D051740:Ikaros Transcription Factor / Q000172:deficiency* / Q000235:genetics; D016399:Lymphoma, T-Cell / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051740:Ikaros Transcription Factor; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse