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To achieve more accurate genetic functional studies
and clinical applications using Cre-loxP system, it was
required a more sophisticated technique that controls the
Cre activation at the precise time and in a specific cell.
An inducible Cre system is controlled by cell-specific
regulatory elements (promoters and enhancers) and
temporally inducible way by exogenous inducer such as
tamoxifen (tam) or tetracycline (tet) [1,10,14-17].
Tamoxifen-inducible Cre system is achieved by
modified Cre protein fused with the estrogen receptor
containing a mutated ligand binding domain (ER-LBD)
[14,15]. The fused Cre protein is called CreER
recombinase, tamoxifen (also known as CreERT, CreERT
) and normally presented in the cytoplasm in a form
that binds to heat shock protein 90 (HSP90). Upon
binding the synthetic steroids (such tamoxifen or 4-
hydoxytamoxifen; 4-OHT), the interaction is disrupted
between HSP90 and CreERT. This causes nuclear
translocation of CreERT and the interaction of Cre with
loxP sites. In this system, tamoxifen is
systemically administered via intraperitoneal injection.
To improve the function of targeted mutagenesis using
CreERT, a new version of CreER, CreERT2 (Cre-ERT2),
that is about ten-folds more sensitive to 4-OHT in vivo
than CreERT has been generated [15,18]. Thus, the use
of CreERT2 is more preferred in several biological
fields.
Another temporal and cell specific inducible system is
tetracycline (Tet) system, also called doxycycline (Dox;
a tetracycline derivative)-inducible Cre system. Dox is
much more cost-effective, usable and efficient in
controlling the Tet receptor (TetR) than tetracycline. This
system is available in two modes, Tet-on and Tet-off,
which permit Dox-dependent gene activation [19,20] or
inactivation [17]. The Tet systems consist of three
elements, reverse tetracycline-controlled transactivator
(rtTA), tetracycline-controlled transactivator (tTA) and
tetracycline responsive element (TRE), also referred to
as a tetracycline operon (TetO), which regulates a cre
gene expression. When the rtTA binds to Dox, it can
bind to the tetO7 (7 repeats of tetO) sequences and
activates Cre gene expression (“Tet-on”) (Figure 2B), on
the other hand, tTA binds to tetO7 sequences in normally,
and when it is coupled with Dox, it can no longer bind
to the tetO7 sequences and inactivates Cre expression
(“Tet-off”). In Tet system, doxycycline is
usually administered in feed or drinking water