p53 (ARF-dependent stabilization pathway)

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CSML1.9 version: ZIP | CSML [2007-06-05]
CSML3.0 version: ZIP | CSML [2008-01-29]
Launch on CIOPlayer [2009-08-05]
Launch on CIO [2009-08-05]

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  • Created by Atsushi Doi.

Description

Proteins p53, MDM2, and p19ARF are proteins closely related to cancer. The protein p53 is a protein which suppresses the formation of tumors, and the protein MDM2 promotes the formation of tumors by decreasing the activity of the protein p53. Understanding of control mechanism of these proteins connects to development of an effective medicine for suppressing the tumor.

It is known that protein p53 works as a transcription factor for many genes [el-Deiry, 1998] and its transcriptional activity is controlled by a complex formed with proteins MDM2 and p19ARF [Zhang and Xiong, 2001; Iwakuma and Lozano, 2003]. However, it is still unclear whether protein p53 keeps its transcriptional activity in the form of the trimer with proteins p53, MDM2 and p19ARF. Figure 1 shows an hybrid functional Petri net (HFPN) model which has been constructed by compiling and interpreting the information of p53-MDM2 interactions in the literature [1,2,3,4,5,6,7,8].

With our HFPN model, we have simulated mutual behaviors between genes p53, MDM2, p19ARF, and their products. Through simulation, we discussed whether the complex p53-MDM2-p19ARF has transcriptional activity for genes Bax and MDM2 or not.

Figure 1: HFPN model of interactions of genes p53, MDM2, and p19ARF and their products. For places and transitions, pictures reflecting biological images are used. An additional name (C) or (N) is attached at the tail of a substance name, when we need to distinguish locations of the substances in the cytoplasm or in the nucleus.

Results

Figure 2 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 considered the following cases:

(1) All genes p53, MDM2, and p19ARF are not expressed (transitions T5, T12, and T14 are deleted).

(2) Only gene p53 is expressed (transitions T12 and T14 are deleted). Genes p53 and MDM2 are expressed (transition T14 is deleted).

(3) The complex p53-MDM2-p19ARF can not activate genes MDM2 and Bax, while all of genes p53, MDM2, and p19ARF are expressed (transitions T19 and T20 are deleted).

(4) The complex p53-MDM2-p19ARF can activate genes MDM2 and Bax, while all of genes p53, MDM2, and p19ARF are expressed.

The simulation results suggested that protein p53 should have the transcriptional activity in the forms of the trimer of proteins p53, MDM2, and p19ARF.

Figure 2: Simulation results of concentration behaviors of p53(N), MDM2(N), p19ARF(N), p53_MDM2_p19ARF, and Bax mRNA on combinations of p53, MDM2, and p19ARF overexpressions. +; overexpress the corresponding gene, –; not overexpress the corresponding gene. Transition of T5, T12, and T14 incorporates to the HFPN model for representing the overexpression of p53, MDM2, and p19ARF. Each of these transitions is removed from the HFPN model in the case of no overexpression of the corresponding gene.

Publication

  • Doi A, Nagasaki M, Matsuno H, Miyano S, Simulation-based validation of the p53 transcriptional activity with hybrid functional Petri net, In Silico Biology, 6(1-2): 0001 (2006).(PubMed_16789909)(.html)

References

  1. Barak Y, Juven T, Haffner R, Oren M, mdm2 expression is induced by wild type p53 activity, EMBO J., 12:461-468, 1993.
  2. Honda R, Tanaka H, Yasuda H, Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53, FEBS Lett., 420:25-27, 1997.
  3. Kamijo T, Weber J D, Zambetti G, Zindy F, Roussel M F, Sherr C J, Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2, Proc. Natl. Acad. Sci. USA, 95(14):8292-8297, 1998.
  4. Miyashita T, Reed J C, Tumor suppressor p53 is a direct transcriptional activator of the human bax gene, Cell, 80:293-299, 1995.
  5. Pomerantz J, Schreiber-Agus N, Liegeois N J, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee H W, Cordon-Cardo C, DePinho R A, The Ink4a tumor suppressor gene product p19Arf interacts with MDM2 and neutralizes MDM2's inhibition of p53, Cell, 92(6):713-723, 1998.
  6. Tao W, Levine A J, P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc. Natl. Acad. Sci. USA, 96: 6937-6941, 1999.
  7. Zhang Y, Xiong Y, Yarbrough W G, ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways, Cell, 92(6):725-734, 1998.
  8. Zhang Y, Xiong Y, Mutation in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53, Mol. Cell, 3: 579-591, 1999.