PMID- 17956344
OWN - NLM
STAT- MEDLINE
DCOM- 20080205
LR  - 20211027
IS  - 0300-5127 (Print)
IS  - 1470-8752 (Electronic)
IS  - 0300-5127 (Linking)
VI  - 35
IP  - Pt 5
DP  - 2007 Nov
TI  - Mouse models for BRAF-induced cancers.
PG  - 1329-33
AB  - Oncogenic mutations in the BRAF gene are detected in approximately 7% of human 
      cancer samples with a particularly high frequency of mutation in malignant 
      melanomas. Over 40 different missense BRAF mutations have been found, but the 
      vast majority (>90%) represent a single nucleotide change resulting in a 
      valine-->glutamate mutation at residue 600 ((V600E)BRAF). In cells cultured in 
      vitro, (V600E)BRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated 
      protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK 
      phosphorylation leading to an increase in cell proliferation, cell survival, 
      transformation, tumorigenicity, invasion and vascular development. Many of these 
      hallmarks of cancer can be reversed by treatment of cells with siRNA (small 
      interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are 
      attractive therapeutic targets in cancer samples with BRAF mutations. In order to 
      fully understand the role of oncogenic BRAF in cancer development in vivo as well 
      as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs 
      (genetically engineered mouse models) have been generated in which expression of 
      oncogenic BRaf is conditionally dependent on the Cre recombinase. The 
      delivery/activation of the Cre recombinase can be regulated in both a temporal 
      and spatial manner and therefore these mouse models can be used to recapitulate 
      the somatic mutation of BRAF that occurs in different tissues in the development 
      of human cancer. The data so far obtained following Cre-mediated activation in 
      haemopoietic tissue and the lung indicate that (V600E)BRAF mutation can drive 
      tumour initiation and that its primary effect is to induce high levels of cyclin 
      D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced 
      senescence) are evident that restrain further development of the tumour.
FAU - Pritchard, C
AU  - Pritchard C
AD  - Department of Biochemistry, Henry Wellcome Building, University of Leicester, 
      Lancaster Road, Leicester LE1 7RH, U.K. cap8@le.ac.uk
FAU - Carragher, L
AU  - Carragher L
FAU - Aldridge, V
AU  - Aldridge V
FAU - Giblett, S
AU  - Giblett S
FAU - Jin, H
AU  - Jin H
FAU - Foster, C
AU  - Foster C
FAU - Andreadi, C
AU  - Andreadi C
FAU - Kamata, T
AU  - Kamata T
LA  - eng
GR  - A6969/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Review
PL  - England
TA  - Biochem Soc Trans
JT  - Biochemical Society transactions
JID - 7506897
RN  - EC 2.7.11.1 (Braf protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
SB  - IM
MH  - Animals
MH  - *Disease Models, Animal
MH  - Mice
MH  - Mutation
MH  - Neoplasms, Experimental/*genetics
MH  - Proto-Oncogene Proteins B-raf/*genetics
PMC - PMC2637606
MID - UKMS3763
OID - NLM: UKMS3763
EDAT- 2007/10/25 09:00
MHDA- 2008/02/06 09:00
PMCR- 2009/02/09
CRDT- 2007/10/25 09:00
PHST- 2007/10/25 09:00 [pubmed]
PHST- 2008/02/06 09:00 [medline]
PHST- 2007/10/25 09:00 [entrez]
PHST- 2009/02/09 00:00 [pmc-release]
AID - BST0351329 [pii]
AID - 10.1042/BST0351329 [doi]
PST - ppublish
SO  - Biochem Soc Trans. 2007 Nov;35(Pt 5):1329-33. doi: 10.1042/BST0351329.