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Series GSE113369 Query DataSets for GSE113369
Status Public on Sep 20, 2018
Title CDK4 inhibition diminishes p53 activation by Mdm2-antagonists
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary CDK4 inhibitors have reached clinical approval for cancer therapy. In parallel, the p53 antagonist Mdm2 remains an attractive target for anti-cancer therapy, including numerous clinical studies. The genes encoding Mdm2 and CDK4 are frequently co-amplified in human malignancies, most notably in liposarcomas, suggesting their combined targeting for therapy. Here we show, however, that small compounds that inhibit Mdm2 and CDK4 antagonize each other rather than synergize in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon Mdm2 inhibition, and similar results were obtained when depleting Mdm2 and/or CDK4 with siRNA. CDK4 inhibitors also interfered with p53 activity in response to DNA damage. CDK4 inhibition did not reduce p53 binding or histone acetylation to promoters, but rather attenuated the subsequent recruitment of RNA polymerase II. The complexes of p53 and Mdm2, as well as CDK4 and Cyclin D1, physically associated with each other. Upon combined inhibition of Mdm2 and CDK4/6, the interaction of this complex was impaired. Thus, the CDK4-Cyclin D1 complex plays a key role in enabling the transcription of p53 target genes. Taken together, our results raise caution regarding the combination of CDK4 inhibitors with Mdm2 antagonists or conventional DNA-damaging chemotherapeutics in the clinics. Moreover, they suggest a hitherto unknown role for CDK4-cyclin D1 complex in sustaining p53 activity, possibly focusing p53-mediated transcription on actively proliferating cells.
 
Overall design Expression profiling by high throughput sequencing. 6 conditions were used for this experiment namely- DMSO, Nutlin, PD0332991 and the combination. SJSA cells were treated with Nutlin for 6 hours (Nutlin); PD0332991, a CDK4/6 inhibitor for a period of 24 or 30 hours (PD24, PD30), and combinations of Nutlin with PD0332991 at both time points (N+PD24 and N+PD30). DMSO is used as control. The libraries were performed in triplicates.
 
Contributor(s) Dobbelstein M, Sriraman A
Citation(s) 30206211
Submission date Apr 19, 2018
Last update date May 09, 2019
Contact name Anusha Sriraman
E-mail(s) asriram@gwdg.de
Phone +4915211841314
Organization name Georg-August University of Göttingen
Department Department of Molecular Oncology
Street address Justus-von-liebig Weg 11
City Göttingen
ZIP/Postal code 37075
Country Germany
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (18)
GSM3104359 DMSO_1
GSM3104360 DMSO_2
GSM3104361 DMSO_3
Relations
BioProject PRJNA450932
SRA SRP141126

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE113369_Basemean_6rep_NUT_PD30_vs_NUT.csv.gz 822.5 Kb (ftp)(http) CSV
GSE113369_Basemean_6rep_PD30_vs_DMSO.csv.gz 835.2 Kb (ftp)(http) CSV
GSE113369_DESeq2_Results_Nut_vs_DMSO.csv.gz 1.4 Mb (ftp)(http) CSV
GSE113369_DMSO_vs_PD24_VSDexp.csv.gz 291.7 Kb (ftp)(http) CSV
GSE113369_DMSO_vs_PD30_VSDexp.csv.gz 291.8 Kb (ftp)(http) CSV
GSE113369_DeSEQ2_Results_DMSO_vs_PD24.csv.xlsx 2.0 Mb (ftp)(http) XLSX
GSE113369_DeSEQ2_Results_DMSO_vs_PD30.csv.xlsx 2.0 Mb (ftp)(http) XLSX
GSE113369_Nut_vs_Nut_PD24_VSDexp.csv.gz 471.0 Kb (ftp)(http) CSV
GSE113369_Nut_vs_Nut_PD30_VSDexp.csv.gz 288.1 Kb (ftp)(http) CSV
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