Posttranslational regulation of Myc by promyelocytic leukemia zinc finger protein.

Full 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.

Author information

Author/s: Shi, Jin (J); Vogt, Peter K (PK);

Affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Oct; vol 125 (issue 7) : pp 1558-65

Dates: Created 2009/08/05; Completed 2009/08/28;

PMID: 19444914, status: MEDLINE (last retrieval date: 8/28/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Phosphorylation
Plasmids
Protein Biosynthesis
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-myc - metabolism
Transcription, Genetic
Up-Regulation

Associated Chemicals: Kruppel-Like Transcription Factors (0) ; Proto-Oncogene Proteins (0) ; Proto-Oncogene Proteins c-myc (0) ; ZBTB16 protein, human (147855-37-6) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.1.37)

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