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We thank T. Berg and C. Rochette-Egly for reagents, P. Munoz-Canoves, S. de la Luna and G. Gil for discussions, S. Colomer-Lahiguera and J. Douet for graphical assistance, V. Valero for technical support and V. A. Raker for helpful discussions about the manuscript. This work was supported by grants from the 'Fondo de Investigacion Sanitario' (FIS, Spanish Ministerio de Sanidad) to S.A.B.; and from the Spanish 'Ministerio de Educacion y Ciencia', AGAUR and 'Fundacio La Marato' to L.D.C. I.U. has been supported by an FPI fellowship of the Spanish Ministerio de Ciencia y Educacion, M.B. by a DFG and a Ramon y Cajal fellowship, S.T. by a 'La Caixa' fellowship and S.D. by a PFIS fellowship.

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E-box-independent regulation of transcription and differentiation by MYC

Publicat a:Nature Cell Biology. 13 (12): 1443-U149 - 2011-12-01 13(12), DOI: 10.1038/ncb2355

Autors: Uribesalgo, Iris; Buschbeck, Marcus; Gutierrez, Arantxa; Teichmann, Sophia; Demajo, Santiago; Kuebler, Bernd; Nomdedeu, Josep F.; Martin-Caballero, Juan; Roma, Guglielmo; Aznar Benitah, Salvador; Di Croce, Luciano;

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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(4). 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-alpha (RAR alpha). MYC MAX cooperates with RAR alpha 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.

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