Human Gene Set: ACOSTA_PROLIFERATION_INDEPENDENT_MYC_TARGETS_DN


Standard name ACOSTA_PROLIFERATION_INDEPENDENT_MYC_TARGETS_DN
Systematic name M2222
Brief description Genes down-regulated in K562 cells (lymphoblast) by MYC [GeneID=4609] in the presence of CKN1B [GeneID=1027].
Full description or abstract Inhibition of differentiation has been proposed as an important mechanism for Myc-induced tumorigenesis, but the mechanisms involved are unclear. We have established a genetically defined differentiation model in human leukemia K562 cells by conditional expression of the cyclin-dependent kinase (Cdk) inhibitor p27 (inducible by Zn(2+)) and Myc (activatable by 4-hydroxy-tamoxifen). Induction of p27 resulted in erythroid differentiation, accompanied by Cdk inhibition and G(1) arrest. Interestingly, activation of Myc inhibited p27-mediated erythroid differentiation without affecting p27-mediated proliferation arrest. Microarray-based gene expression indicated that, in the presence of p27, Myc blocked the upregulation of several erythroid-cell-specific genes, including NFE2, JUNB, and GATA1 (transcription factors with a pivotal role in erythropoiesis). Moreover, Myc also blocked the upregulation of Mad1, a transcriptional antagonist of Myc that is able to induce erythroid differentiation. Cotransfection experiments demonstrated that Myc-mediated inhibition of differentiation is partly dependent on the repression of Mad1 and GATA1. In conclusion, this model demonstrates that Myc-mediated inhibition of differentiation depends on the regulation of a specific gene program, whereas it is independent of p27-mediated cell cycle arrest. Our results support the hypothesis that differentiation inhibition is an important Myc tumorigenic mechanism that is independent of cell proliferation.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 18838534   Authors: Acosta JC,Ferrándiz N,Bretones G,Torrano V,Blanco R,Richard C,O'Connell B,Sedivy J,Delgado MD,León J
Exact source Table 3S: fold change (log2) < 0
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Source species Homo sapiens
Contributed by Arthur Liberzon (MSigDB Team)
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identifier namespace		 Human_NCBI_Gene_ID
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