TY - JOUR
T1 - E-box-independent regulation of transcription and differentiation by MYC
AU - Uribesalgo, Iris
AU - Buschbeck, Marcus
AU - Gutiérrez, Arantxa
AU - Teichmann, Sophia
AU - Demajo, Santiago
AU - Kuebler, Bernd
AU - Nomdedéu, Josep F.
AU - Marté-N-Caballero, Juan
AU - Roma, Guglielmo
AU - Benitah, Salvador Aznar
AU - Di Croce, Luciano
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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-α (RARα). MYC,MAX cooperates with RARα 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.
AB - 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-α (RARα). MYC,MAX cooperates with RARα 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.
U2 - 10.1038/ncb2355
DO - 10.1038/ncb2355
M3 - Article
VL - 13
SP - 1443
EP - 1449
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 12
ER -