Biomedical Engineering Reference
In-Depth Information
activation by RAF [15]. The RAF/MEK interaction is required for the
phosphorylation of ERK1/2, which is crucial to cell cycle progression
through the G1/S phase [22]. While activation of ERK 1/2 is
dependent on the adhesion to the extracellular matrix, the BRAF
V600E mutation forgoes this step. Therefore, ERK 1/2 is able to be
activated without the ECM and the constitutively activated mutated
BRAF allows for up regulated progression through the cell-cycle
[23]. Constitutive activity in the Ras/Raf/MEK/ERK MAPK pathway
contributes to the oncogenic phenotype of melanoma through its
effects on cell proliferation, invasion and survival.
17.3
BRAF V600E Mutation in Melanoma
As already mentioned, the most common mutation to be reported in
melanoma is in BRAF with at least 60% of all melanomas possessing
activating mutations in the BRAF gene [13]. Among these, the BRAF
V600E mutation, consisting of a valine to glutamic acid substitution,
make up over 80% of the BRAF mutations [13]. More than 75 somatic
mutations in the BRAF gene have been identified in melanoma,
and all mutations at V600 in Exon 15 constitutively activate BRAF.
The hypothesized mechanism for the uncontrolled activation is
the increased accessibility of the activation segment when a small
hydrophobic amino acid at 600 (valine) is switched to a hydrophilic
residue (glutamic acid) [24]. The mutated BRAF corresponds to a
constitutively active MAPK pathway and thus promoting cell cycle
entry and cell proliferation through the up-regulation of cyclin D1
expression and down-regulation of the cyclin-dependent kinase
inhibitor, p27(Kip1) [25].
The pathophysiology of how the activated BRAF V600E mutation
leads to abnormal melanocyte growth and thus melanoma may not
be clear as a multitude of factors are involved. However, there is
evidence that one of the pro-apoptotic proteins of the BCL-2 family,
BIM, plays a role in the BRAF-mediated pathway [26]. The BCL-2
family of proteins is an important regulator of apoptosis including
molecules that promote cell growth or cell death [27]. BIM induces
apoptosis by antagonizing the anti-apoptotic proteins, BCL-2,
BCL-XL and MCL-1 [28]. In relation to melanomas with the BRAF
V600E mutation, the BRAF/MEK/ERK signaling pathway has been
shown to inhibit the expression of pro-apoptotic BIM in mouse and
