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Modeling the interplay between the HIF-1 and p53 pathways in hypoxia.

Zhou CH, Zhang XP, Liu F, Wang W - Sci Rep (2015)

Bottom Line: How the two transcription factors interact to determine cell fates is less well understood.Here, we developed a network model to characterize crosstalk between the HIF-1 and p53 pathways, taking into account that HIF-1α and p53 are targeted for proteasomal degradation by Mdm2 and compete for binding to limiting co-activator p300.We showed that both the transrepression and transactivation activities of p53 promote apoptosis induction.

View Article: PubMed Central - PubMed

Affiliation: National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China.

ABSTRACT
Both the hypoxia-inducible factor-1 (HIF-1) and tumor suppressor p53 are involved in the cellular response to hypoxia. How the two transcription factors interact to determine cell fates is less well understood. Here, we developed a network model to characterize crosstalk between the HIF-1 and p53 pathways, taking into account that HIF-1α and p53 are targeted for proteasomal degradation by Mdm2 and compete for binding to limiting co-activator p300. We reported the network dynamics under various hypoxic conditions and revealed how the stabilization and transcriptional activities of p53 and HIF-1α are modulated to determine the cell fate. We showed that both the transrepression and transactivation activities of p53 promote apoptosis induction. This work provides new insight into the mechanism for the cellular response to hypoxia.

No MeSH data available.


Related in: MedlinePlus

Interplay between HIF-1α and p53 in anoxia.(A) Bifurcation diagrams of [p53pac] (red), [HIF-1αac] (blue) and [Mdm2n] (green) versus the amount of p300. (B) Bifurcation diagrams of [p53pac] (red), [HIF-1αac] (blue), [Mdm2c] (green) and [Mdm2n] (pink) versus the p53-induced production rate of Mdm2, ksmdm2. (C) Bifurcation diagrams of [HIF-1αac] (blue, on the right axis), [p53pac] (red) and [PUMA] (green) versus the production rate of HIF-1α, kshif. (D) Bifurcation diagrams of [HIF-1αac] (blue), [p53pac] (red) and [PUMA] (green) versus the production rate of p53, ksp53.
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f5: Interplay between HIF-1α and p53 in anoxia.(A) Bifurcation diagrams of [p53pac] (red), [HIF-1αac] (blue) and [Mdm2n] (green) versus the amount of p300. (B) Bifurcation diagrams of [p53pac] (red), [HIF-1αac] (blue), [Mdm2c] (green) and [Mdm2n] (pink) versus the p53-induced production rate of Mdm2, ksmdm2. (C) Bifurcation diagrams of [HIF-1αac] (blue, on the right axis), [p53pac] (red) and [PUMA] (green) versus the production rate of HIF-1α, kshif. (D) Bifurcation diagrams of [HIF-1αac] (blue), [p53pac] (red) and [PUMA] (green) versus the production rate of p53, ksp53.

Mentions: As mentioned above, p53 and HIF-1α compete for limiting p300 to activate their transcriptional activity and are targeted for degradation by Mdm2. Here, we explore their interplay under anoxia. We first investigate how the p300 level influences the steady-state concentrations of proteins (Fig. 5A). With increasing [p300], [p53pac] continuously rises toward saturation. [Mdm2n] remains at a low level over a wide range since Mdm2np predominates in the nucleus. Intriguingly, [HIF-1αac] first rises, then drops, and rises again with increasing [p300]. Since ATR is fully activated and [p53p] is large enough under anoxia, increasing [p300] leads to enhancement of p53 acetylation. When [p300] is very low, the level of unacetylated HIF-1α is sufficiently high, and [HIF-1αac] rises with increasing [p300]. When [p300] further rises, [p53pac] is elevated and HIF-1α is markedly degraded by p53-induced Mdm2, leading to a drop in [HIF-1αac]. If p300 is in excess, more HIF-1α is acetylated, resulting in a continuous rise in [HIF-1αac] with increasing [p300]. The intricate effect of p300 level on the acetylation of HIF-1α is worth testing experimentally.


Modeling the interplay between the HIF-1 and p53 pathways in hypoxia.

Zhou CH, Zhang XP, Liu F, Wang W - Sci Rep (2015)

Interplay between HIF-1α and p53 in anoxia.(A) Bifurcation diagrams of [p53pac] (red), [HIF-1αac] (blue) and [Mdm2n] (green) versus the amount of p300. (B) Bifurcation diagrams of [p53pac] (red), [HIF-1αac] (blue), [Mdm2c] (green) and [Mdm2n] (pink) versus the p53-induced production rate of Mdm2, ksmdm2. (C) Bifurcation diagrams of [HIF-1αac] (blue, on the right axis), [p53pac] (red) and [PUMA] (green) versus the production rate of HIF-1α, kshif. (D) Bifurcation diagrams of [HIF-1αac] (blue), [p53pac] (red) and [PUMA] (green) versus the production rate of p53, ksp53.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561886&req=5

f5: Interplay between HIF-1α and p53 in anoxia.(A) Bifurcation diagrams of [p53pac] (red), [HIF-1αac] (blue) and [Mdm2n] (green) versus the amount of p300. (B) Bifurcation diagrams of [p53pac] (red), [HIF-1αac] (blue), [Mdm2c] (green) and [Mdm2n] (pink) versus the p53-induced production rate of Mdm2, ksmdm2. (C) Bifurcation diagrams of [HIF-1αac] (blue, on the right axis), [p53pac] (red) and [PUMA] (green) versus the production rate of HIF-1α, kshif. (D) Bifurcation diagrams of [HIF-1αac] (blue), [p53pac] (red) and [PUMA] (green) versus the production rate of p53, ksp53.
Mentions: As mentioned above, p53 and HIF-1α compete for limiting p300 to activate their transcriptional activity and are targeted for degradation by Mdm2. Here, we explore their interplay under anoxia. We first investigate how the p300 level influences the steady-state concentrations of proteins (Fig. 5A). With increasing [p300], [p53pac] continuously rises toward saturation. [Mdm2n] remains at a low level over a wide range since Mdm2np predominates in the nucleus. Intriguingly, [HIF-1αac] first rises, then drops, and rises again with increasing [p300]. Since ATR is fully activated and [p53p] is large enough under anoxia, increasing [p300] leads to enhancement of p53 acetylation. When [p300] is very low, the level of unacetylated HIF-1α is sufficiently high, and [HIF-1αac] rises with increasing [p300]. When [p300] further rises, [p53pac] is elevated and HIF-1α is markedly degraded by p53-induced Mdm2, leading to a drop in [HIF-1αac]. If p300 is in excess, more HIF-1α is acetylated, resulting in a continuous rise in [HIF-1αac] with increasing [p300]. The intricate effect of p300 level on the acetylation of HIF-1α is worth testing experimentally.

Bottom Line: How the two transcription factors interact to determine cell fates is less well understood.Here, we developed a network model to characterize crosstalk between the HIF-1 and p53 pathways, taking into account that HIF-1α and p53 are targeted for proteasomal degradation by Mdm2 and compete for binding to limiting co-activator p300.We showed that both the transrepression and transactivation activities of p53 promote apoptosis induction.

View Article: PubMed Central - PubMed

Affiliation: National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China.

ABSTRACT
Both the hypoxia-inducible factor-1 (HIF-1) and tumor suppressor p53 are involved in the cellular response to hypoxia. How the two transcription factors interact to determine cell fates is less well understood. Here, we developed a network model to characterize crosstalk between the HIF-1 and p53 pathways, taking into account that HIF-1α and p53 are targeted for proteasomal degradation by Mdm2 and compete for binding to limiting co-activator p300. We reported the network dynamics under various hypoxic conditions and revealed how the stabilization and transcriptional activities of p53 and HIF-1α are modulated to determine the cell fate. We showed that both the transrepression and transactivation activities of p53 promote apoptosis induction. This work provides new insight into the mechanism for the cellular response to hypoxia.

No MeSH data available.


Related in: MedlinePlus