期刊
NATURE CELL BIOLOGY
卷 13, 期 12, 页码 1443-U149出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2355
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类别
资金
- 'Fondo de Investigacion Sanitario' (FIS, Spanish Ministerio de Sanidad)
- Spanish 'Ministerio de Educacion y Ciencia', AGAUR
- Fundacio La Marato
- Spanish Ministerio de Ciencia y Educacion
- DFG
- Ramon y Cajal fellowship
- 'La Caixa' fellowship
- PFIS
- ICREA Funding Source: Custom
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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