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Posttranslational regulation of myc by promyelocytic leukemia zinc finger protein

Academic Article
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Overview

authors

  • Shi, J.
  • Vogt, Peter K.

publication date

  • October 2009

journal

  • International Journal of Cancer  Journal

abstract

  • The promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, induces cellular resistance to oncogenic transformation by diverse oncoproteins. Two point mutants of PLZF that have lost the antioncogenic activity of the wild-type protein are oncogenic in chicken embryo fibroblasts; this activity is correlated with differential effects on Myc. Wild-type PLZF represses Myc transcription without affecting total Myc protein levels and reduces the levels of phosphorylated Myc. The PLZF mutants do not alter Myc transcription or protein expression but increase the levels of phosphorylated Myc. These modifications of Myc are correlated with PLZF-induced changes in Akt and the mitogen-activated protein kinase (MAPK) pathway. Wild-type PLZF downregulates the MAPK pathway and activates Akt, resulting in reduced phosphorylation on serine 62 of Myc by Erk and on threonine 58 by glycogen synthase kinase 3beta. The mutants fail to activate Akt and only slightly downregulate phospho-Erk. We postulate that the 2 PLZF mutants are oncogenic, because they function as dominant negatives of wild-type PLZF, enhancing Myc phosphorylation and increasing Myc transcriptional and oncogenic activity. In support of this suggestion, a specific inhibitor of Myc is able to revert the transformed phenotype of PLZF mutant-expressing cells.

subject areas

  • Blotting, Northern
  • Blotting, Western
  • Down-Regulation
  • Gene Expression Regulation, Leukemic
  • Humans
  • Kruppel-Like Transcription Factors
  • Mitogen-Activated Protein Kinase Kinases
  • Phosphorylation
  • Plasmids
  • Protein Biosynthesis
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-myc
  • Transcription, Genetic
  • Up-Regulation
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Research

keywords

  • dominant negative PLZF
  • oncogenic transformation
  • phosphorylation
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Identity

PubMed Central ID

  • PMC2721905

International Standard Serial Number (ISSN)

  • 0020-7136

Digital Object Identifier (DOI)

  • 10.1002/ijc.24449

PubMed ID

  • 19444914
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Additional Document Info

start page

  • 1558

end page

  • 1565

volume

  • 125

issue

  • 7

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