Abstract:
:B-RAF is a serine/threonine-specific protein kinase that is mutated in approximately 70% of human melanomas. However, the role of this signalling molecule in cancer is unclear. Here, we show that ERK is constitutively activated in melanoma cells expressing oncogenic B-RAF and that this activity is required for proliferation. B-RAF depletion by siRNA blocks ERK activity, whereas A-RAF and C-RAF depletion do not affect ERK signalling. B-RAF depletion inhibits DNA synthesis and induces apoptosis in three melanoma cell lines and we show that the RAF inhibitor BAY43-9006 also blocks ERK activity, inhibits DNA synthesis and induces cell death in these cells. BAY43-9006 targets B-RAF signalling in vivo and induces a substantial growth delay in melanoma tumour xenografts. Our data demonstrate that oncogenic B-RAF activates ERK signalling, induces proliferation and protects cells from apoptosis, demonstrating that it is an important therapeutic target and thus provides novel strategies for clinical management of melanoma and other cancers.
journal_name
Oncogenejournal_title
Oncogeneauthors
Karasarides M,Chiloeches A,Hayward R,Niculescu-Duvaz D,Scanlon I,Friedlos F,Ogilvie L,Hedley D,Martin J,Marshall CJ,Springer CJ,Marais Rdoi
10.1038/sj.onc.1207785subject
Has Abstractpub_date
2004-08-19 00:00:00pages
6292-8issue
37eissn
0950-9232issn
1476-5594pii
1207785journal_volume
23pub_type
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