Journal
ONCOGENE
Volume 27, Issue 22, Pages 3122-3133Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210972
Keywords
B-Raf(V600E); ERK; mps1; spindle checkpoint; melanoma
Funding
- NIGMS NIH HHS [GM62542] Funding Source: Medline
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The B-Raf(V600E) mutant, found in 65% of human melanomas, drives constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and is implicated in tumorigenesis. Recently, we showed that B-Raf is important for spindle formation and the mitotic spindle checkpoint arrest. In this study, we demonstrate that B-Raf(V600E) signaling deregulates the spindle checkpoint as a consequence of stabilizing monopolar spindle 1 (Mps1) levels in human melanoma cells. Upon introducing the B-Raf(V600E) mutant into wild-type B-Raf melanoma cells, Mps1 protein and activity increased 3- and 10-fold, respectively. In addition, Mps1 became hyperphosphorylated, which correlated with stabilization of Mps1 protein levels. In contrast, reduction of B-Raf by RNAi or inactivation of ERK by the MEK inhibitor U0126 resulted in a precipitous decline in Mps1 levels. Together, these results suggest that B-Raf signaling through ERK regulates the stability of Mps1. Finally, B-Raf(V600E) expression induces a mitotic delay due to promoting robust activation of the mitotic spindle checkpoint. These effects were dependent on the induction of Mps1 levels by oncogenic B-Raf(V600E) as shown by depleting Mps1 with short interfering RNA. Collectively, our findings implicate a new mechanism through which B-Raf(V600E) exerts its oncogenic effects in melanoma.
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