Simulation-Based Validation of the p53 Transcriptional Activity with Hybrid Functional Petri Net - Biological Petri Nets - page 138

Fig. 4. Interactions of p53, MDM2, and ARF described in KEGG. Simplified information between two proteins is presented.

Figure 3(3) shows that MDM2(N) accumulates more in the nucleus compared to that of Fig. 3(2) when
genes MDM2 and p53 are expressed. In contrast, the concentration of protein p53(N) becomes lower
compared to its concentration in Fig. 3(2).
On the assumption that gene MDM2 is not knocked out in our model, protein MDM2 is accumulated
(Fig. 3(2)) in the nucleus due to the activation of MDM2 by p53 in the nucleus ( T 18 ). As shown in
Fig. 3(2), although protein p53 concentrates in the nucleus, it rapidly decreases after reaching the peak.
This decrease is caused by protein MDM2 that ubiquitinates protein p53 exported to the cytoplasm from
the nucleus. This low concentration of protein p53 causes the low level expression of gene Bax .In
Fig. 3(3), we can observe that protein p53 keeps at lower concentration level in the nucleus than Fig. 3(2).
This reduction of protein p53 results from the expression of gene MDM2 .
Figure 3(4) and 3(5) show the case when all of genes p53 , MDM2 , and p19ARF are expressed under
two different assumptions on the transcriptional activity of the complex p53-MDM2-p19ARF.
- High accumulation of the complex p53 MDM2 p19ARF is observed under the assumption that the
complex p53-MDM2-p19ARF has no transcriptional activity for genes MDM2 and Bax (Fig. 3(4)).
Besides, both of the accumulation of protein p53(N) and the expression of Bax mRNA keep in low
level.
- In contrast, when we assume the transcriptional activity of the complex p53-MDM2-p19ARF for
MDM2 and Bax genes (Fig. 3(5)), lower accumulation of p53 MDM2 p19ARF is observed. In
addition, both of the accumulation of MDM2(N) and the expression of Bax mRNA grow rapidly
and keep in higher level in comparison with the case of Fig. 3(4).

OTHER DESCRIPTIONS ON p53, MDM2 AND p19ARF INTERACTIONS

Figure 4 is the part of molecular interactions in KEGG [Kanehisa and Goto, 2000], ( http://www.genome.
jp/kegg/pathway/hsa/hsa04110.html ) which shows the relationship between p53 and MDM2. 2 In gen-
eral, biological interactions to repress gene products are not restricted to one kind of effect: a protein A
represses the expression of a gene B , and a protein A represses the activities of a protein B and so on.
Figure 4 does not give any specific information for the repression of p53 by MDM2.
Figure 5 is the part of the pathway about p53 in TRANSPATH [Krull et al. , 2003], ( http://www.

biobase.de/ ) . Although this map describes the information on the complex formation of MDM2 and

2 To unify the symbols used in this paper, we use “MDM2” instead of “Mdm2” written in KEGG and TRANSPATH. In
addition, “ARF” in KEGG and TRANSPATH involves both meanings of p14ARF and p19ARF [Zhang and Xiong, 2001].