p38MAPK delta controls c-Myb degradation in response to stress.
The c-myb gene is the progenitor of the v-myb oncogene, which causes avian myelomonocytic leukemia. Dysregulated c-myb gene expression is linked to the development of myeloid leukemia in mice and is predictive of poor prognosis in human colorectal cancer. Among the variety of post-translational modifications controlling the c-Myb protein, phosphorylation was shown to affect the transactivation activity and the rate of protein degradation. In this work we show that phosphorylation of c-Myb in response to stress led to rapid protein degradation, which occurred via a proteasome-dependent pathway. The kinases principally involved in this response were p38MAPK delta and, to a lesser extent, p38MAPK gamma. To assess whether c-Myb degradation was driven by changes in the overall level of phosphorylation or rather by phosphorylation at specific sites we systematically mutated potential sites of phosphorylation fulfilling the consensus for recognition by MAPKs (Ser/Thr-Pro). Among the point mutants examined, residues located downstream to the transactivation domain appeared to be essential for c-Myb stability. Particularly, mutation of Thr(354), Thr(486), Ser(556) and Thr(572) to Alanine conferred resistance to stress-induced degradation. The implications of c-Myb downregulation during inflammatory responses are discussed.
Pani
Elisabetta
E
Institute of Molecular Cancer Research, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
Ferrari
Stefano
S
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D048292:Mitogen-Activated Protein Kinase 13 / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D020598:Proto-Oncogene Proteins c-myb; D019319:Okadaic Acid; D000841:Anisomycin; D048292:Mitogen-Activated Protein Kinase 13