P38MAPKδ controls c-Myb degradation in response to stress

Abstract

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 p38MAPKδ and, to a lesser extent, p38MAPKγ. 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.