Raf kinases and cancer

Excerpt

The Raf oncoprotein family of serine/threonine kinases comprises three members in higher vertebrates: A-Raf, B-Raf, and C-Raf. Raf kinases have been shown to play pivotal roles in the regulation of cell proliferation, differentiation, and apoptosis. They are essential components of the Ras/Raf/MEK/ERK kinase cascade, which transmits signals from activated cell surface receptors to transcription factors into the nucleus. Raf signaling pathways are often aberrantly activated in human tumors. Recently, B-Raf kinase was identified as a novel mutational and therapeutic target in human melanoma and other types of cancer. Several drugs interfering with Raf kinase signaling are currently under investigation in clinical trials. We have established a Raf-dependent transgenic mouse lung cancer model and have provided evidence that the additional loss of the p53 tumor suppressor gene in these mice accelerates tumor formation and induces a phenotypic switch. In addition, by analyzing downstream effectors of Raf kinases we have identified a connection between hypermitogenic signaling and the regulation of Polycomb group (PcG) proteins. PcG family members are known to be part of a cellular memory system that maintains transcription patterns and cell identity through cell divisions. …