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Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Senawong, Thanaset Phuchareon, Janyaporn Ohara, Osamu Mccormick, Frank Rauen, Katherine A. Tetsu, Osamu |
| Copyright Year | 2008 |
| Abstract | Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder characterized by distinctive craniofacial features, heart defects, mental retardation and ectodermal abnormalities. We recently reported missense germline mutations in the genes MEK1 and MEK2 in patients with CFC. These mutations, including F53S and Y130C MEK1, and F57C MEK2, are the first naturally occurring mutations to be identified in these genes. This study reports data concerning the biochemical functions of the novel mutants, as well as the roles of these MEK genes in the MAPK signaling cascade. Our CFC MEK variants cannot induce ERK unless they are phosphorylated by RAF at two key serine residues in the regulatory loop. When we replaced the serine residues with alanines, ERK phosphorylation was significantly reduced in the presence of RAF. We did find that F57C MEK2 activation was less dependent on RAF signaling than the other mutants. This difference results in F57C MEK2 being resistant to the selective RAF inhibitor SB-590885. All three mutants are sensitive to the MEK inhibitor U0126. The majority of CFC cases result from mutations in B-RAF. A recent report indicates the possibility that cancer cells with activated B-RAF have enhanced, selective sensitivity to MEK inhibitors. Thus, regardless of mutations identified in an individual with CFC, MEK inhibition is a potential therapeutic approach for this population. |
| Starting Page | 392 |
| Ending Page | 403 |
| Page Count | 12 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/hmg/17/3/10.1093/hmg/ddm319/2/ddm319.pdf?Expires=1491347133&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q&Signature=GnDE9ZDinnWAaQl-mZO2A4yBHKJXWfgr8U7m4EEvYkG~Uo48I2T-colJapzfPFbZ5kazSG65gNKRaxi2fYPQKzmzzj1MCKx-IMjwYxu53l5kiyM0-HUmAofqwCMxrwQ-dLJatG5f1nVHP23ytr7W2YdFk3d3RmHlaHDdJwu200Tui-8yAfpIVpEJy3czsU3w5H1E~7CiYH0XvLGJK074VjywsHsuBsD-gvc0ZZe7j~GB94aJ4mU2qH-ofuRE2eq0oWqDs8PXgYNNrgezFCPv1ZMt9UEdRS4-EiaPzosp-oxHXX7LT2ANNdZzqiN2VtBOmLSfcWfNkk8jPGeAcqgizg__ |
| PubMed reference number | 17981815v1 |
| Volume Number | 17 |
| Issue Number | 3 |
| Journal | Human molecular genetics |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Cardio-facio-cutaneous syndrome Cascade Device Component Christ-Siemens-Touraine syndrome Congenital Abnormality Congenital Heart Defects Developmental Disabilities Ectoderm Germ-Line Mutation MAP kinase kinase activity MAP2K2 wt Allele Mental Retardation Mitogen-Activated Protein Kinase Kinases Patients RAF1 wt Allele SB-590885 U 0126 mutant |
| Content Type | Text |
| Resource Type | Article |
