E-box-independent regulation of transcription and differentiation by MYC.
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-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.
Centre de Regulació Genòmica and UPF, Barcelona 08003, Spain.
Iris
I
Uribesalgo
Marcus
M
Buschbeck
Arantxa
A
Gutiérrez
Sophia
S
Teichmann
Santiago
S
Demajo
Bernd
B
Kuebler
Josep F
JF
Nomdedéu
Juan
J
Martín-Caballero
Guglielmo
G
Roma
Salvador Aznar
SA
Benitah
Luciano
L
Di Croce
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D024721:E-Box Elements / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D018922:HL-60 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C000715470:MAS1 protein, human; C499330:MAX protein, human; C489427:MYC protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C515907:PAK2 protein, human; D054462:p21-Activated Kinases