Dual regulation of Myc by Abl

V. J. Sanchez-Arévalo Lobo, M. Doni, A. Verrecchia, S. Sanulli, G. Fagà, A. Piontini, M. Bianchi, M. Conacci-Sorrell, G. Mazzarol, V. Peg, J. H. Losa, P. Ronchi, M. Ponzoni, R. N. Eisenman, C. Doglioni, B. Amati

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The tyrosine kinase c-Abl (or Abl) and the prolyl-isomerase Pin1 cooperatively activate the transcription factor p73 by enhancing recruitment of the acetyltransferase p300. As the transcription factor c-Myc (or Myc) is a known target of Pin1 and p300, we hypothesized that it might be regulated in a similar manner. Consistent with this hypothesis, overexpression of Pin1 augmented the interaction of Myc with p300 and transcriptional activity. The action of Abl, however, was more complex than predicted. On one hand, Abl indirectly enhanced phosphorylation of Myc on Ser 62 and Thr 58, its association with Pin1 and p300 and its acetylation by p300. These effects of Abl were exerted through phosphorylation of substrate(s) other than Myc itself. On the other hand, Abl interacted with the C-terminal domain of Myc and phosphorylated up to five tyrosine residues in its N-terminus, the principal of which was Y74. Indirect immunofluorescence or immunohistochemical staining suggested that the Y74-phosphorylated form of Myc (Myc-pY74) localized to the cytoplasm and coexisted either with active Abl in a subset of mammary carcinomas or with Bcr-Abl in chronic myeloid leukemia. In all instances, Myc-pY74 constituted a minor fraction of the cellular Myc protein. Thus, our data unravel two potential effects of Abl on Myc: first, Abl signaling can indirectly augment acetylation of Myc by p300, and most likely also its transcriptional activity in the nucleus; second, Abl can directly phosphorylate Myc on tyrosine: the resulting form of Myc appears to be cytoplasmic, and its presence correlates with Abl activation in cancer.

Original languageEnglish (US)
Pages (from-to)5261-5271
Number of pages11
JournalOncogene
Volume32
Issue number45
DOIs
StatePublished - Nov 7 2013

Keywords

  • Breast Cancer
  • CML
  • Pin1
  • c-Abl
  • c-Myc

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Sanchez-Arévalo Lobo, V. J., Doni, M., Verrecchia, A., Sanulli, S., Fagà, G., Piontini, A., Bianchi, M., Conacci-Sorrell, M., Mazzarol, G., Peg, V., Losa, J. H., Ronchi, P., Ponzoni, M., Eisenman, R. N., Doglioni, C., & Amati, B. (2013). Dual regulation of Myc by Abl. Oncogene, 32(45), 5261-5271. https://doi.org/10.1038/onc.2012.621