01. Gene therapy Boulikas.pdf - Gene therapy & Molecular Biology

Figure 23. A pathway leading to the induction of growth
arrest and apoptosis by the cytokines TNF-α, IL-1β, and IFN-γ.
The pathway is conserved between mammalian cells and yeast.
Adapted from Nickels and Broach (1996). From Boulikas T
(1997) Gene therapy of prostate cancer: p53, suicidal genes, and
other targets. Anticancer Res 17, 1471-1506. Reproduced with
the kind permission from Anticancer Research.
serine/threonine protein kinase termed GCK-related
(GCKR) most likely signals via mitogen-activated protein
kinase (MAPK)/extracellular signal-regulated kinase
(ERK) kinase kinase 1 (MEKK1) to activate the SAPK
pathway (Shi and Kehrl, 1997).
D. NF-κB as anti-apoptotic molecule and
TNF-α signaling
Activation of NF-κB is believed to lead to the
activation of antiapoptotic genes that have not been fully
identified. The antiapoptotic role of NF-κB at the
molecular level and the TNF-α connection consists of the
following events; signaling by TNF-α induces
trimerization of its receptors, an event causing three
different cascades: (i) Activation of IκB kinase and
activation of NF-κB, a pathway which prevents cell death.
A key step for NF-κB activation leading to the activation
of the stress-activated protein kinase (SAPK, also called c-
Jun N-terminal kinase or JNK) is the recruitment to the
TNF receptor of TNF receptor-associated factor 2
(TRAF2). (ii) induction of apoptosis via a different
pathway involving activation of sphingomyelinase in
plasma membrane and generation of ceramide leading to
EGFR activation and induction of apoptosis; (iii)
activation of MEKK1 and JNK protein kinases which is
not linked to apoptotic death but to AP-1 activation
(Figure 24). The antiapoptotic function of NF-κB may
involve activation of the manganese superoxide dismutase
and of the zinc finger protein A20; expression of these
genes is induced by TNF and each of them provides
protection against apoptosis (Liu et al, 1996).
bcl-2 upregulation during progression of prostate
cancer was implicated in the acquisition of the androgenindependent
growth; a strong antioxidant that interferes
Gene Therapy and Molecular Biology Vol 1, page 67
67
with activation of NF-κB in prostate carcinoma cells,
potentiated TNF-α-stimulated apoptosis signaling through
a bcl-2-regulated mechanism; based on these studies,
modulation of the NF-κB survival signaling was proposed
to be used to clinical advantage in the treatment of prostate
cancer patients (Herrmann et al, 1997).
Transgenic mice lacking the p65 (RelA) subunit of
NF-κB displayed increased apoptosis and degeneration in
the liver providing further support to an apoptotic function
of NF-κB (Beg et al, 1995). The TNF-induced death of
mouse primary fibroblasts expressing deregulated c-Myc
was inhibited by transient overexpression of the p65
subunit of NF-κB, which increased NF-κB activity in the
cells (Klefstrom et al, 1997). Rel (a protooncogene,
member of the NF-κB family) is implicated in both
positive and negative regulation of GM-CSF expression in
a variety of cell types (Gerontakis et al, 1996).
The elucidation of IL-1, TNF, IFN and other signaling
pathways would lead to the discovery of new drugs
causing specific inhibition; for example, members of the
IL-1 signaling cascade may provide therapeutic targets for
inhibiting IL-1-induced inflammation (Muzio et al, 1997).