Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation

被引:72
作者
Robinson, J. P. [1 ]
VanBrocklin, M. W. [1 ]
Guilbeault, A. R. [1 ]
Signorelli, D. L. [1 ]
Brandner, S. [2 ]
Holmen, S. L. [1 ]
机构
[1] Nevada Canc Inst, Drug Dev Dept, Las Vegas, NV 89135 USA
[2] UCL, Inst Neurol, Dept Neurogenerat Dis, Div Neuropathol, London, England
关键词
glioma; BRAF; KRas; Akt; Ink4a; Arf; SPINDLE-CELL GLIOBLASTOMA; B-RAF GENE; PROTEIN-KINASE; NEGATIVE REGULATION; PATHWAY ACTIVATION; NEURAL PROGENITORS; TUMOR SUPPRESSION; MAPK PATHWAY; KRAS; PHOSPHORYLATION;
D O I
10.1038/onc.2009.333
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations in receptor tyrosine kinase (RTK) growth factor receptors (epidermal growth factor receptor, platelet-derived growth factor receptor, MET and ERBB2), which result in downstream activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral replication-competent avian leukosis virus long terminal repeat, splice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in Ink4a/Arf(lox/lox) mice in vivo. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with Ink4a/Arf loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not Ink4a/Arf loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy. Oncogene (2010) 29, 335-344; doi:10.1038/onc.2009.333; published online 26 October 2009
引用
收藏
页码:335 / 344
页数:10
相关论文
共 51 条
[1]   Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma [J].
Aguirre, AJ ;
Bardeesy, N ;
Sinha, M ;
Lopez, L ;
Tuveson, DA ;
Horner, J ;
Redston, MS ;
DePinho, RA .
GENES & DEVELOPMENT, 2003, 17 (24) :3112-3126
[2]   Tumour cell survival signalling by the ERK1/2 pathway [J].
Balmanno, K. ;
Cook, S. J. .
CELL DEATH AND DIFFERENTIATION, 2009, 16 (03) :368-377
[3]   THE MOUSE B-RAF GENE ENCODES MULTIPLE PROTEIN ISOFORMS WITH TISSUE-SPECIFIC EXPRESSION [J].
BARNIER, JV ;
PAPIN, C ;
EYCHENE, A ;
LECOQ, O ;
CALOTHY, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (40) :23381-23389
[4]   Mutation analysis of B-RAF gene in human gliomas [J].
Basto, D ;
Trovisco, V ;
Lopes, JM ;
Martins, A ;
Pardal, F ;
Soares, P ;
Reis, RM .
ACTA NEUROPATHOLOGICA, 2005, 109 (02) :207-210
[5]   Delivery of short hairpin RNA sequences by using a replication-competent avian retroviral vector [J].
Bromberg-White, JL ;
Webb, CP ;
Patacsil, VS ;
Miranti, CK ;
Williams, BO ;
Holmen, SL .
JOURNAL OF VIROLOGY, 2004, 78 (09) :4914-4916
[6]   The INK4a/ARF tumor suppressor: one gene - two products - two pathways [J].
Chin, L ;
Pomerantz, J ;
DePinho, RA .
TRENDS IN BIOCHEMICAL SCIENCES, 1998, 23 (08) :291-296
[7]   Positive and negative regulation of Raf kinase activity and function by phosphorylation [J].
Chong, H ;
Lee, J ;
Guan, KL .
EMBO JOURNAL, 2001, 20 (14) :3716-3727
[8]  
DAHLSTRAND J, 1992, CANCER RES, V52, P5334
[9]   Astrocyte differentiation states and glioma formation [J].
Dai, C ;
Holland, EC .
CANCER JOURNAL, 2003, 9 (02) :72-81
[10]   The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats [J].
Dai, CK ;
Lyustikman, Y ;
Shih, A ;
Hu, XY ;
Fuller, GN ;
Rosenblum, M ;
Holland, EC .
NEOPLASIA, 2005, 7 (04) :397-406