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Title: Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.
Author: Velho, Sérgia
Oliveira, Carla
Paredes, Joana
Sousa, Sónia
Leite, Marina
Matos, Paulo
Milanezi, Fernanda
Ribeiro, Ana Sofia
Mendes, Nuno
Licastro, Danilo
Karhu, Auli
Oliveira, Maria José
Ligtenberg, Marjolijn
Hamelin, Richard
Carneiro, Fátima
Lindblom, Annika
Peltomaki, Paivi
Castedo, Sérgio
Schwartz, Simó Jr
Jordan, Peter
Aaltonen, Lauri A.
Hofstra, Robert M.W.
Suriano, Gianpaolo
Stupka, Elia
Fialho, Arsenio M
Seruca, Raquel
Keywords: Vias de Transdução de Sinal e Patologias Associadas
Issue Date: 15-Feb-2010
Publisher: Oxford University Press
Citation: Hum Mol Genet. 2010 Feb 15;19(4):697-706. Epub 2009 Dec 2
Abstract: Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase, regulating MAPkinase signalling, in which cancer-associated mutations have never been reported. In this study, 174 primary gastrointestinal cancers (48 hereditary and 126 sporadic forms) and 7 colorectal cancer cell lines were screened for MLK3 mutations. MLK3 mutations were significantly associated with MSI phenotype in primary tumours (P = 0.0005), occurring in 21% of the MSI carcinomas. Most MLK3 somatic mutations identified were of the missense type (62.5%) and more than 80% of them affected evolutionarily conserved residues. A predictive 3D model points to the functional relevance of MLK3 missense mutations, which cluster in the kinase domain. Further, the model shows that most of the altered residues in the kinase domain probably affect MLK3 scaffold properties, instead of its kinase activity. MLK3 missense mutations showed transforming capacity in vitro and cells expressing the mutant gene were able to develop locally invasive tumours, when subcutaneously injected in nude mice. Interestingly, in primary tumours, MLK3 mutations occurred in KRAS and/or BRAF wild-type carcinomas, although not being mutually exclusive genetic events. In conclusion, we have demonstrated for the first time the presence of MLK3 mutations in cancer and its association to mismatch repair deficiency. Further, we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant.
Peer review: yes
ISSN: 0964-6906
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Appears in Collections:DGH - Artigos em revistas internacionais

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