Abstract
Myc is a highly unstable transcription factor that is destroyed by ubiquitin (Ub)-mediated proteolysis. We have previously identified an amino-terminal ‘degron’ within Myc that signals its destruction; this degron spans the transcriptional activation domain of Myc, and includes two highly conserved regions called Myc boxes I and II. We now report the identification of a second element – the D-element – which is also required for Myc proteolysis. The centrally located D-element is distinct from the PEST domain in Myc, but includes Myc box III, a third highly conserved region with no previously known function. We show that deletion of the D-element stabilizes the Myc protein without affecting its ubiquitylation, and report that the D-element and the degron act in a cell-type-specific manner to direct Myc proteolysis. These data thus demonstrate that Myc stability is regulated at both the ubiquitylation and postubiquitylation levels, and reveal that substrates of the Ub – proteasome system can be targeted for destruction differently in different cell types.
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Acknowledgements
We thank C Bautista, D Bohmann, D Conklin, S Elledge, G Hannon, and R Whitaker for reagents. We thank D Conklin, W Herr, A Krainer, S Lowe, and K Tworkowski for comments on the manuscript. AH was supported by the Deutsche Forschungsgemeinschaft. WPT is a Leukemia and Lymphoma Society Scholar. This work was supported by the CSHL Cancer Center Support Grant CA45508 and by US Public Health Service grant CA-13106 from the National Cancer Institute.
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Herbst, A., Salghetti, S., Kim, S. et al. Multiple cell-type-specific elements regulate Myc protein stability. Oncogene 23, 3863–3871 (2004). https://doi.org/10.1038/sj.onc.1207492
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DOI: https://doi.org/10.1038/sj.onc.1207492
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