Regulation of c-myc stability by selective stress conditions and by MEKK1 requires aa 127-189 of c-myc.

Alarcon-Vargas D, Tansey WP, Ronai Z
Oncogene. 2002 21 (28): 4384-91

PMID: 12080469 · DOI:10.1038/sj.onc.1205543

C-myc availability is central for its ability to serve as a regulator of cell growth and death. Here we study the regulation of c-myc protein stability and identify domains of c-myc that are important for its stabilization in response to stress kinases activated following selective stress conditions. UV-irradiation elicited an increase in c-myc protein levels, which could be attenuated by inhibitors of stress kinases but also by actinomycin D-inhibitor of transcription. Inhibition of protein synthesis results in a noticeable decrease in c-myc levels, further pointing to the short half-life of the protein. However, in combination with tumor necrosis factor-alpha (TNF-alpha), cycloheximide efficiently increases steady-state levels of c-myc, suggesting that selective stress conditions are required to increase c-myc protein stability. Expression of MEKK1, an upstream regulator of protein kinases that has been implicated in mediating the response to diverse stress conditions, also results in an efficient increase in the half-life of c-myc protein. To map c-myc domains that are responsive to stress kinases, we monitored changes in the level of c-myc deletion mutants following MEKK1 expression. Of the seven c-myc deletion mutants analysed, the domain spanning amino acids 127-189 was found to be required for MEKK1-dependent increase in c-myc stability. In all, the present study identifies a novel domain that is important for the regulation of c-myc stability by stress kinases in response to selective stress conditions.

MeSH Terms (25)

Antineoplastic Agents Apoptosis Calcium-Calmodulin-Dependent Protein Kinases Cells, Cultured Cycloheximide Dactinomycin Dose-Response Relationship, Drug Electrophoresis, Polyacrylamide Gel Enzyme Inhibitors Fibroblasts Flavonoids Humans Imidazoles MAP Kinase Kinase Kinase 1 Oligopeptides Peptide Fragments Protein-Serine-Threonine Kinases Protein-Tyrosine Kinases Protein Synthesis Inhibitors Proto-Oncogene Proteins c-myc Pyridines Stress, Physiological Tumor Necrosis Factor-alpha Tyrphostins Ultraviolet Rays

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