Thursday, March 24, 2011
Figure 1. Oncolytic control. Macrophages are
first transfected with a vector (light grey rectangle) in which the gene
encoding the adenovirus
small early region 1A (E1A) protein
(yellow oval) is under the control of a hypoxic response element (HRE). They
are then co-transduced with a conditionally competent, oncolytic adenovirus
(Ad; dark grey rectangle)-the replication of which can be regulated by either
E1A protein or a regulatory sequence called PPT. PPT is a composite of promoter
enhancers from three genes expressed in prostate tumor cells: TCR-g alternate reading frame protein (TARP), prostate-specific antigen (KLK3; PSA) and prostate-specific membrane antigen (PSMA; FOLH1; GCPII).
In regions of low oxygen, macrophages upregulate a
transcription factor called hypoxia-inducible factor 1 (HIF1; light blue oval)
which binds the HRE to produce E1A protein [a]. Production of E1A
(yellow oval) then initiates adenovirus replication in the macrophage, leading
to virus production [b].
The virus is then released and can enter
surrounding cells. When the virus enters normal cells, lack of either E1A or
the prostate-specific factors that stimulate the PPT sequence prevents further
viral replication [c]. When the virus enters a prostate cancer cell, the
PPT sequence is activated (dark green oval), leading to a further round of
replication of the oncolytic virus and then cell death [d].
In regions of normal oxygen, macrophages do not upregulate
HIFs. As a result, E1A and adenovirus production do not occur.