Gene Set: KUMAMOTO_RESPONSE_TO_NUTLIN_3A_DN

Standard name KUMAMOTO_RESPONSE_TO_NUTLIN_3A_DN
Systematic name M6379
Brief description Genes down-regulated in response to nutlin-3a [PubChem=216345], an inhibitor of MDM2 [GeneID=4193], in skin fibroblast cultures after knockdown of TP53 [GeneID=7157] by RNAi.
Full description or abstract Nutlin-3, an MDM2 inhibitor, activates p53, resulting in several types of cancer cells undergoing apoptosis. Although p53 is mutated or deleted in approximately 50% of all cancers, p53 is still functionally active in the other 50%. Consequently, nutlin-3 and similar drugs could be candidates for neoadjuvant therapy in cancers with a functional p53. Cellular senescence is also a phenotype induced by p53 activation and plays a critical role in protecting against tumor development. In this report, we found that nutlin-3a can induce senescence in normal human fibroblasts. Nutlin-3a activated and repressed a large number of p53-dependent genes, including those encoding microRNAs. mir-34a, mir-34b, and mir-34c, which have recently been shown to be downstream effectors of p53-mediated senescence, were up-regulated, and inhibitor of growth 2 (ING2) expression was suppressed by nutlin-3a treatment. Two candidates for a p53-DNA binding consensus sequence were found in the ING2 promoter regulatory region; thus, we performed chromatin immunoprecipitation and electrophoretic mobility shift assays and confirmed p53 binding directly to those sites. In addition, the luciferase activity of a construct containing the ING2 regulatory region was repressed after p53 activation. Antisense knockdown of ING2 induces p53-independent senescence, whereas overexpression of ING2 induces p53-dependent senescence. Taken together, we conclude that nutlin-3a induces senescence through p53 activation in normal human fibroblasts, and p53-mediated mir34a, mir34b, and mir34c up-regulation and ING2 down-regulation may be involved in the senescence pathway.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 18451145   Authors: Kumamoto K,Spillare EA,Fujita K,Horikawa I,Yamashita T,Appella E,Nagashima M,Takenoshita S,Yokota J,Harris CC
Exact source Table 1
Related gene sets (show 1 additional gene sets from the source publication)

(show 10 gene sets from the same authors)
External links  
Filtered by similarity
Organism Homo sapiens
Contributed by Jessica Robertson (MSigDB Team)
Source platform Human_RefSeq
Dataset references  
Download gene set format: grp | text | gmt | gmx | xml
Compute overlaps (show collections to investigate for overlap with this gene set)
Compendia expression profiles GTEx compendium
Human tissue compendium (Novartis)
Global Cancer Map (Broad Institute)
NCI-60 cell lines (National Cancer Institute)
Advanced query Further investigate these 10 genes
Gene families Categorize these 10 genes by gene family
Show members (show 10 members mapped to 10 genes)
Version history 3.0: First introduced

See MSigDB license terms here. Please note that certain gene sets have special access terms.