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Mastermind-Like 3 controls proliferation and differentiation in neuroblastoma

  • Noorjahan Basheer
    ,
  • Guus J.J.E. Heynen
    ,
  • Ekaterina Nevedomskaya
    ,
  • Sander Palit
    ,
  • Cor Lieftink
    ,
  • Andreas Schlicker
  • Netherlands Cancer Institute
Research Output: Contribution to journal Article Peer-review

Open access

Abstract

Neuroblastoma cell lines can differentiate upon treatment with retinoic acid (RA), a finding that provided the basis for the clinical use of RA to treat neuroblastoma. However, resistance to RA is often observed, which limits its clinical utility. Using a gain-of-function genetic screen, we identified an unexpected link between RA signaling and mastermindlike 3 (MAML3), a known transcriptional coactivator for NOTCH. Our findings indicate that MAML3 expression leads to the loss of activation of a subset of RA target genes, which hampers RA-induced differentiation and promotes resistance to RA. The regulatory DNA elements of this subset of RA target genes show overlap in binding of MAML3 and the RA receptor, suggesting a direct role for MAML3 in the regulation of these genes. In addition, MAML3 has RA-independent functions, including the activation of IGF1R and downstream AKT signaling via upregulation of IGF2, resulting in increased proliferation. These results demonstrate an important mechanistic role for MAML3 in proliferation and RA-mediated differentiation.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 411-422

Journal (Volume, Issue Number)

Molecular Cancer Research (Volume 14, Issue 5)

Publication milestones

  • Accepted/In press - 08/01/2016
  • Published - 19/01/2016

Publication status

Published - 19/01/2016

ISSN

1541-7786

External Publication IDs

  • handle.net: 10547/624674
  • Scopus: 84969206864

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