Biology Reference
In-Depth Information
ribonucleotide reductase, thymidylate synthetase, and dihydrofolate reductase,
DNA initiation factors such as MCM3 and MCM7, the enzyme DNA polymerase
alpha, and the cell cycle control proteins such as cyclin E, cdk-2, and E2F (Salvant
et al. 1998; Gribaudo et al. 2000; Song and Stinski 2002). Since HCMV infects
terminally differentiated cells of the host that are in the Go phase of the cell cycle,
the virus requires a mechanism to overcome cellular quiescence. The IE86 protein-
along with the IE72 protein and the viral tegument protein pp71-induce cell cycle
progression by inactivating the cellular Rb family of repressor proteins.
N F
κ
-B Promoters
After HCMV infection, gene microarray assays also demonstrated a fourfold or
greater decrease of at least 134 cellular mRNAs (Zhu et al. 1998). Repression of
some cellular genes would favor viral replication. In cells infected with an IE2-86
mutant virus lacking amino acids 136-290 (referred to as delta SX) (Sanchez
et al. 2002), HMGA2 expression is not significantly reduced, suggesting that
the IE86 protein is involved in the regulation of the HMGA2 expression (see the
chapter by V. Sanchez and D.H. Spector, this volume). Repression of select
cytokine and chemokine expression would favor survival of the virus-infected
cell. HCMV infection attenuates interleukin (IL)-1 beta and tumor necrosis factor
(TNF)-alpha proinflammatory signaling (Jarvis et al. 2006; Montag et al. 2006).
The IE86 protein inhibits the induction of interferon (IFN)-beta, TNF-alpha,
RANTES, MIG, MCP-2, and IL-6 (Taylor and Bresnahan 2005, 2006). The effect
of IE86 is downstream of the inhibitor of kappa B (I
κ
B) kinase. While IE86
directly effects the binding of NF
κ-B to its cognate site on the DNA by an
unknown mechanism (Taylor and Bresnahan 2006), IE86 also blocks the activity
of NF
κ-B when the cellular transcription factor is brought to the promoter via a
GAL4 DNA-binding domain (Gealy et al. 2007). Therefore, the inhibition of
NF
κ-B by IE86 is also subsequent to NF
κ-B binding. The regions required to
inhibit NF
κ-B activity are amino terminal of the IE86 carboxyl activation domain
(Gealy et al. 2007). The exact region of the IE86 protein involved in blocking
NF
κ-B activity requires further investigation.
Cell Cycle Progression
CMVs typically infect terminally differentiated cells in the Go/G1 phase of the cell
cycle. The pool of dideoxynucleotide triphosphates and biosynthetic enzymes to
make precursors for DNA synthesis are low in these cells. Since CMVs do not
encode many of the biosynthetic enzymes for DNA precursor synthesis, the virus
must have a mechanism to overcome G1 arrest. The effect of HCMV infection on
the cell cycle is reviewed (see the chapter by V. Sanchez and D.H. Spector, this
volume). As discussed above, the IE86 protein binds to pRb and activates E2F
