HES1 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
S1PR3 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
ID1 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
HSPA5 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
FAM46C DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
LZTFL1 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
ABCA1 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
SLC1A4 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
EEA1 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
SUSD4 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
RCBTB2 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
RHOU DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
TXNIP UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
E2F7 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
CCR9 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
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. Experiment Overall Design: Three independent cultures of the MOLT4 cell line before and 48 hours after addition of the gamma-secretase inhibitor DAPT (5 uM).
ELOVL4 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
NOTCH3 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
RGCC UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
FKBP11 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
MYO7B DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
DTX1 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
(Sample) cell type/T-cell acute lymphoblastic leukemia cell
T-cell acute lymphoblastic leukemia cell
TOB1 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
Analysis of '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
HES4 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
P2RX5 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
MIER1 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
RASGRP1 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
MYCN DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
DAAM2 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
CEP128 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
BAHCC1 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
LINC01215 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
(Factor value) COMPOUND/gamma-secretase inhibitor DAPT 5
BCL11A UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
MSH6 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
CR2 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
CD82 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
RAG1 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
SATB1 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
TANC1 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
CXXC5 UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
SH2D1A UP in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
SH3TC1 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'
CD55 DOWN in '5 micromolar gamma-secretase inhibitor DAPT' vs 'none'