E-box-independent regulation of transcription and differentiation by MYC
Por:
Uribesalgo I., Buschbeck M., Gutiérrez A., Teichmann S., Demajo S., Kuebler B., Nomdedéu J.F., Marté-N-Caballero J., Roma G., Benitah S.A., Di Croce L.
Publicada:
1 ene 2011
Resumen:
MYC proto-oncogene is a key player in cell homeostasis that is commonly deregulated in human carcinogenesis 1. MYC can either activate or repress target genes by forming a complex with MAX (ref.2). MYC also exerts MAX-independent functions that are not yet fully characterized 3. Cells possess an intrinsic pathway that can abrogate MYC,MAX dimerization and E-box interaction, by inducing phosphorylation of MYC in a PAK2-dependent manner at three residues located in its helix,loop,helix domain. Here we show that these carboxy-terminal phosphorylation events switch MYC from an oncogenic to a tumour-suppressive function. In undifferentiated cells, MYC,MAX is targeted to the promoters of retinoic-acid-responsive genes by its direct interaction with the retinoic acid receptor-a (RARa). MYC,MAX cooperates with RARa to repress genes required for differentiation, in an E-box-independent manner. Conversely, on C-terminal phosphorylation of MYC during differentiation, the complex switches from a repressive to an activating function, by releasing MAX and recruiting transcriptional co-activators. Phospho-MYC synergizes with retinoic acid to eliminate circulating leukaemic cells and to decrease the level of tumour invasion. Our results identify an E-box-independent mechanism for transcriptional regulation by MYC that unveils previously unknown functions for MYC in differentiation. These may be exploited to develop alternative targeted therapies. © 2011 Macmillan Publishers Limited. All rights reserved.
Filiaciones:
Uribesalgo I.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Buschbeck M.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Institute for Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona 08916, Spain
Gutiérrez A.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Teichmann S.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Demajo S.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Kuebler B.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Nomdedéu J.F.:
Department of Laboratory of Hematology, Institute of Biomedical Research (IIB Sant Pau), Universitat Auténoma de Barcelona, Barcelona 08025, Spain
Marté-N-Caballero J.:
Unidad de Animal de Laboratorio, PRBB, Barcelona 08003, Spain
Roma G.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Benitah S.A.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Institució Catalana de Recerca i Estudis Avanéats (ICREA), Barcelona, Spain
Di Croce L.:
Centre de Regulació Genómica (CRG) and UPF, Barcelona 08003, Spain
Institució Catalana de Recerca i Estudis Avanéats (ICREA), Barcelona, Spain
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