Abstract
Mutations in the ERK pathway occur in approximately one-third of all human cancers and most often involve production of mutant RAS or BRAF. Several studies, including our own, have shown that mutations in the
BRAF and
RAS genes are generally mutually exclusive. This study was performed to determine the relative oncogenic potential of the
BRAF and
RAS oncogenes.
BRAF
V600E
-,
H-RAS
G12V
-, and
N-RAS
Q61R
-transfected mouse embryonic fibroblasts (MEFs) that lack p53 (p53
−/−) or contain mutations at codon 172 (p53
R172H and p53
R172P) were able to induce morphologically transformed foci in p53
−/− and p53
R172H MEFs but not in p53
R172P MEFs. Interestingly,
BRAF
V600E
was less potent than mutant
H-RAS
G12V
or
N-RAS
Q61R
was in cooperating with mutant p53 as the numbers and sizes of foci induced by
BRAF
V600E
were significantly lower and smaller.
In vitro growth characteristics and anchorage-independent growth of transfected MEFs corroborated the transformed phenotype, and
in vivo tumorigenesis confirmed the results. These results indicate that mutant
BRAF
V600E
is weakly oncogenic compared with mutant
RAS and that they both cooperate with p53
−/− and p53
R172H but not with p53
R172P in oncogenic transformation.
