Biology Reference
In-Depth Information
apoptosis. Many viruses encode proteins that target the PI3K/Akt
pathway because of the central role it plays in regulating host cell
survival. The HCV NS5A protein associates with the p85 regulatory
subunit of PI3K to promote the PI3K/Akt-mediated BAD inactiva-
tion.
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The HBx protein also promotes cell survival through this
pathway by inactivating caspase 3, which is a central effector mole-
cule in apoptosis. The HEV ORF3 protein also activates Akt and
phosphorylation of its downstream substrates (Jameel; unpublished).
While this is generally understood to promote cell survival, the
mechanistic details are not yet clear.
Regulation of the NF
κ
B Pathway
Transcription factor NF
B induces the expression of multiple genes
whose products function in a variety of pathways ranging from cell
survival and proliferation to the regulation of immune and inflamma-
tory responses.
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NF
κ
B is activated in response to various stimuli, and
the signal transduction pathways involve different signaling proteins
such as the NF
κ
B-inducing kinase (NIK), mitogen-activated protein
kinase/extracellular signal-regulated kinase kinase 1 (MEKK1), IL-1
receptor-associated kinase (IRAKs), protein kinase C (PKC), trans-
forming growth factor
κ
-activated kinase (TAK1), TNF receptor-
associated factor (TRAF) and many others that converge centrally on
the I
β
B plays a crucial role
in control of cell proliferation and survival by inducing the expres-
sion of cyclin D1, c-myc and other positive regulators of the cell cycle.
It also activates the expression of anti-apoptotic genes whose products
include members of the Bcl2 family, such as Bcl-X
L
, A1, Bfl1, and cel-
lular inhibitors of apoptosis (c-IAP1, c-IAP2 and XIAP), TRAF1,
TRAF2 and FLICE-inhibitory protein cFLICE. Different viruses use
this dynamic pathway to prolong the survival of host cells to enable
the virus to complete its replication cycle and establish infection in the
host. The HBx protein is a potent inducer of NF
κ
B kinase (IKK) signaling complex.
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NF
κ
B and is believed
to play a critical role in hepatocarcinogenesis during chronic HBV
infection.
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HBx activates NF
κ
B by MEKK-1 activation mediated by
the Ras and the PKC pathways. The expression of HCV proteins is
κ
