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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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Demajo, SantiagoAuthor
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Article

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

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

Authors: 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;

Affiliations

;CRG, Barcelona 08003, Spain      Centre de Regulacio Genomica (CRG)    Pompeu Fabra University    Barcelona Institute of Science & Technology;UPF, Barcelona 08003, Spain      Pompeu Fabra University      ;Inst Predict & Personalized Med Canc IMPPC, Barcelona 08916, Spain;Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Inst Biomed Res IIB St Pau, Dept Lab Hematol, Barcelona 08025, Spain      Autonomous University of Barcelona    Hospital of Santa Creu i Sant Pau;PRBB, Unidad Anim Lab, Barcelona 08003, Spain      Pompeu Fabra University      ;ICREA, Barcelona, Spain - Author
CRG, Barcelona 08003, Spain.      Barcelona Institute of Science & Technology    Pompeu Fabra University    Centre de Regulacio Genomica (CRG) - Author

Abstract

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.

Keywords
Acute promyelocytic leukemiaCo-repressorComplexDna-bindingHistone deacetylaseInhibitionReceptorsResponse elementsRetinoic acidThyroid-hormone

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature Cell Biology due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2011, it was in position 6/181, thus managing to position itself as a Q1 (Primer Cuartil), in the category Cell Biology.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 3.2, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-20, the following number of citations:

  • WoS: 27
  • Scopus: 34
  • Europe PMC: 30
  • OpenCitations: 38
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-20:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 89 (PlumX).