BRAF inactivation drives aneuploidy by deregulating CRAF.
Aspartate-594 is the third most common BRAF residue mutated in human cancer. Mutants of this residue are kinase inactive, and the mechanism(s) by which they contribute to cancer has remained perplexing. Using a conditional knock-in mouse model, we show that the (D594A)Braf mutant does not drive tumor development per se but is able to induce aneuploidy in murine splenocytes and mouse embryonic fibroblasts and contributes to immortalization through the propagation of aneuploid cells. (D594A)Braf lacks kinase activity but induces the related gene product Craf as well as the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway. Here, we show that the aneuploid phenotype is dependent on Craf. Treatment with the MEK inhibitor U0126 did not attenuate the emergence of aneuploidy but prevented the growth of aneuploid cells. These results provide a previously unidentified link between Craf and chromosomal stability, with important implications for our understanding of the development of cancers with driver mutations that hyperactivate Craf.
Department of Biochemistry, University of Leicester, Leicester, United Kingdom.
Tamihiro
T
Kamata
Jahan
J
Hussain
Susan
S
Giblett
Robert
R
Hayward
Richard
R
Marais
Catrin
C
Pritchard
D000782:Aneuploidy; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D043171:Chromosomal Instability; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics* / Q000378:metabolism
D048008:TNF Receptor-Associated Factor 3; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases