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Series GSE6495 Query DataSets for GSE6495
Status Public on Dec 15, 2006
Title NOTCH signaling in T-cell acute lymphoblastic leukemia cell lines
Organism Homo sapiens
Experiment type Expression profiling by array
Summary In T-cell acute lymphoblastic leukemia (T-ALL) NOTCH 1 receptors are frequently mutated. This leads to aberrantly high Notch signaling, but how this translates into deregulated cell cycle control and the transformed cell type is poorly understood. In this report, we analyze downstream responses resulting from the high level of NOTCH 1 signaling in T-ALL. Notch activity, measured immediately downstream of the NOTCH 1 receptor, is high, but expression of the canonical downstream Notch response genes HES 1 and HEY 2 is low both in primary cells from T-ALL patients and in T-ALL cell lines. This suggests that other immediate Notch downstream genes are activated, and we found that Notch signaling controls the levels of expression of the E3 ubiquitin ligase SKP2 and its target protein p27Kip1. We show that in T-ALL cell lines, recruitment of NOTCH 1 ICD to the SKP2 promoter was accompanied by high SKP2 and low p27Kip1 protein levels were low. In contrast, pharmacologically blocking Notch signaling reversed this picture and led to loss of NOTCH 1 ICD occupancy of the SKP2 promoter, decreased SKP2 and increased p27Kip1 expression. T-ALL cells show a rapid G1-S cell cycle transition, while blocked Notch signaling resulted in G0/G1 cell cycle arrest, also observed by transfection of p27Kip1 or, to a smaller extent, a dominant negative SKP2 allele. Collectively, our data suggest that the aberrantly high Notch signaling in T-ALL maintains SKP2 at a high level and reduces p27Kip1, which leads to more rapid cell cycle progression.
Keywords: comparative genomic hybridization
Overall design Three independent cultures of the MOLT4 cell line before and 48 hours after addition of the gamma-secretase inhibitor DAPT (5 uM).
Contributor(s) Dohda T, Maljukova A, Liu L, Heyman M, Grandér D, Brodin D, Sangfelt O, Lendahl U
Citation(s) 17560996
Submission date Dec 10, 2006
Last update date Mar 25, 2019
Contact name David Brodin
Phone +46058583726
Organization name Karolinska Institute
Department Department of biosciences and Nutrition
Lab Affymetrix lab
Street address Halsovagen 7-9
City Stockholm
ZIP/Postal code S-141 57 Huddinge
Country Sweden
Platforms (1)
GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array
Samples (6)
GSM149395 MOLT4_ctrl_A
GSM149396 MOLT4_ctrl_B
GSM149397 MOLT4_ctrl_C
BioProject PRJNA98665

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Supplementary file Size Download File type/resource
GSE6495_RAW.tar 24.7 Mb (http)(custom) TAR (of CEL)

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