Biology Reference
In-Depth Information
Our HFPN pathway model involves knowledge about protein subcellular localization, process of form-
ing protein complexes, and functional molecular interaction. Starting from a qualitative pathway model,
we manually tuned the parameters for the transitions and initial conditions on places in the HFPN model
so that the model is consistent with the data in [Pomerantz
et al.
, 1998]. Thus it also involves knowl-
edge about system dynamics. The HFPN model in Fig. 2 is available from
http://genomicobject.net/
,
http://genomicobject.net/˜gon/p53/
including all parameters in the model and can be simulated on Cell
Illustrator 2.0 (
http://www.fqspl.com.pl/?a=product view&id=20&lang=en
)
.
Transcriptional activity of p53-MDM2-p19ARF complex on MDM2 and Bax
For the transcriptional activity of the complex p53-MDM2-p19ARF, two cases opposite to each other
can be considered: the p53-MDM2-p19 complex can activate
MDM2
and
Bax
or can not activate them.
It is confirmed that the complex of proteins p53 and MDM2 has no transcriptional activity on
MDM2
and
Bax
[Oliner
et al.
, 1993; Honda
et al.
, 1997], while protein p53 itself has transcriptional activity on
them [Barak
et al.
, 1993; Miyashita and Reed, 1995]. This change on the p53 transcriptional activity
results from the binding of protein MDM2 to the site of protein p53 which is also the transactivation
domain for downstream genes. From this fact, it is natural to consider that protein p53 loses its
transcriptional activity by forming the complex with protein MDM2. However, we find the following
observations in the literature which are contradictory to the above fact:
A. Protein p53 accumulates in the nucleus when both proteins p19ARF and MDM2 exist in the cell
[Pomerantz
et al.
, 1998; Zhang and Xiong, 1999; Zhang and Xiong, 2001].
B. When plenty of protein p53 exist in the nucleus, an increase of p53 transcriptional activity can be
observed [Pomerantz
et al.
, 1998].
On the assumption that p53 itself and the complex p53-MDM2 do not accumulate enough to have
transcriptional activity through translocation of the p53-MDM2 complex from the nucleus to the cyto-
plasm, we may consider that in A)-B), protein p53 forms the complex p53-MDM2-p19ARF with proteins
MDM2 and p19ARF. This may mean that the complex p53-MDM2-p19ARF has transcriptional activity
on genes
MDM2
and
Bax
.
The next section shows simulations on the HFPN model of Fig. 2. The simulation results suggested
that the complex p53-MDM2-p19ARF should have the transcriptional activity on genes
MDM2
and
Bax
.
SIMULATION AND RESULTS
Figure 3 shows the results of simulations, where concentration behaviors of p53(N), MDM2(N),
p19ARF(N), p53 MDM2 p19ARF, and Bax mRNA are observed in the following combinations of three
genes expressions;
p53
,
MDM2
, and
p19ARF
. We introduced gene
Bax
in the HFPN model in order to
detect the expression level of gene
p53
. We suppose that a cell is rich in an amount of ubiquitin (the
initial value of the place for ubiquitin is set to be 100). We considered the following cases:
1. All genes
p53
,
MDM2
, and
p19ARF
are not expressed (transitions
T
5
,
T
12
, and
T
14
are deleted).
2. Only gene
p53
is expressed (transitions
T
12
and
T
14
are deleted).
3. Genes
p53
and
MDM2
are expressed (transition
T
14
is deleted).
4. The complex p53-MDM2-p19ARF can not activate genes
MDM2
and
Bax
, while all of genes
p53
,
MDM2
, and
p19ARF
are expressed (transitions
T
19
and
T
20
are deleted).
