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

Abstract

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-α), 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.

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Acknowledgements

We thank Mitch Goldfarb and Lu Hai Wang for advice, and Zhen Qian Pan, Serge Fuchs and members of the Ronai lab for discussions. We thank Alisa Helfgott for technical assistance. Support from NCI grants (CA85197 to D Alarcon-Vargas; CA78419 to Z Ronai; CA13106 to WP Tansey; a Leukemia and Lymphoma Society Scholar) is greatly acknowledged.

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Correspondence to Ze'ev Ronai.

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Alarcon-Vargas, D., Tansey, W. & Ronai, Z. Regulation of c-myc stability by selective stress conditions and by MEKK1 requires aa 127–189 of c-myc. Oncogene 21, 4384–4391 (2002). https://doi.org/10.1038/sj.onc.1205543

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Keywords

  • c-myc
  • stress kinases
  • MEKK1
  • protein stability
  • cytokines
  • TNFα

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