Biomedical Engineering Reference
In-Depth Information
B functional activity by oncoproteins often
lags behind the significantly clearer understanding of pathways associated with
cytokine and LPS-induction of NF-
The mechanisms of stimulation of NF-
κ
κ
B. One of the better understood mechanisms
for the activation of NF-
B by an oncoprotein is the mechanism whereby the
human T cell leukaemia virus type I (HTLV-I) Tax protein activates NF-
κ
B. This
protein directly binds and activates the IKK complex [104]. The MALT1/c-IAP2
fusion found in certain lymphomas leads to ubiquitination of NEMO and subse-
quent NF-
κ
B activation [108]. In addition to the known responses of oncoproteins
in activating NF-
κ
κ
B, evidence has been presented that certain tumor suppressors
can block NF-
B activation. For example, the tumor suppressor ARF has been
reported to inhibit NF-
κ
κ
B through a mechanism involving phosphorylation of
Thr505 on p65 downstream of ATR and Chk1 (
Chapter 5
) [109].
B is activated (i.e., nuclear) in a number of tumors
are consistent with a role for NF-
Studies showing that NF-
κ
κ
B in cancer, although some tumor cell lines exhibit
NF-
B activity without significant nuclear accumulation. Adding further complexity,
the p50 subunit of NF-
κ
B appears to facilitate both the positive and negative regu-
lation of the expression of the KAI1 tumor suppressor gene. Expression of
κ
-catenin
converts the p50 transcriptional complex to a repressive complex through loss of
Tip60 coactivator association and recruitment of transcriptional corepressors, leading
to loss of expression of KAI1 [110].
Given the important role that growth factors play in promoting oncogenesis, it
is not surprising that several growth factors have been shown to activate NF-
β
B. For
example, Biswas and colleagues [111] have shown that EGF can activate NF-
κ
B in
certain cell types. We have provided evidence that EGF can induce recruitment of
p65 to the EAAT2 promoter through a mechanism independent of I
κ
B degradation
[112]. Finally, we and others have shown that PDGF can induce NF-
κ
κ
B activation
and promote c-myc transcription [103].
While there is strong evidence that NF-
B promotes oncogenesis in a variety
of tumors, evidence has been presented that inhibition of NF-
κ
B in skin promotes
mechanism to explain this concept is that inhibition of NF-
κ
B in the skin leads to
JNK activation [114], a finding consistent with several reports that NF-
κ
B activation
suppresses the phosphorylation and activation of JNK. Similar questions regarding
the oncogenic potential of NF-
κ
B appears
to function downstream of the tumor suppressor p53. Vousden and colleagues [115]
have presented evidence that NF-
κ
B arise with the consideration that NF-
κ
B activation is required downstream of p53 in
order for this tumor suppressor to induce apoptosis. Hung and colleagues [116] have
reported that the oncoprotein
κ
β
-catenin can block NF-
κ
These findings suggest that NF-
κ
B can, under certain conditions, also function as a
tumor suppressor [117].
8.3.2
M
ODES
OF
A
CTION
OF
NF-
κ
B
IN
C
ANCER
AND
C
ANCER
T
HERAPY
R
ESISTANCE
Clearly, NF-
B functions as a transcriptional regulator in a variety of cancer cells
as evidenced through the identification of cancer-specific cancer-relevant gene targets
κ
