RT Journal Article
SR Electronic
T1 BRAF Inactivation Drives Aneuploidy by Deregulating CRAF
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 8475
OP 8486
DO 10.1158/0008-5472.CAN-10-0603
VO 70
IS 21
A1 Kamata, Tamihiro
A1 Hussain, Jahan
A1 Giblett, Susan
A1 Hayward, Robert
A1 Marais, Richard
A1 Pritchard, Catrin
YR 2010
UL http://cancerres.aacrjournals.org/content/70/21/8475.abstract
AB 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 D594ABraf 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. D594ABraf 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. Cancer Res; 70(21); 8475–86. ©2010 AACR.