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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

Protein dynamics and apoptosis induction under severe hypoxia.(A–D) Color-coded concentrations of ATRp (A), p53pac (B), BIM (C) and PUMA (D) as a function of oxygen concentration and time. (E) The timing of Casp3 activation versus oxygen concentration. (F) Time courses of [Casp3] with oxygen concentration at 0.01% (green), 0.018% (blue), or 0.02% (red).
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f4: Protein dynamics and apoptosis induction under severe hypoxia.(A–D) Color-coded concentrations of ATRp (A), p53pac (B), BIM (C) and PUMA (D) as a function of oxygen concentration and time. (E) The timing of Casp3 activation versus oxygen concentration. (F) Time courses of [Casp3] with oxygen concentration at 0.01% (green), 0.018% (blue), or 0.02% (red).

Mentions: Under severe hypoxia, ATR is activated, and thus p53 is stabilized by phosphorylation. For oxygen concentration below 0.025%, [ATRp] quickly rises to plateau levels (Fig. 4A). ATR is partly activated when oxygen concentration is between 0.01% and 0.025%, or is fully activated when oxygen concentration is below 0.01%. Compared with ATRp, p53pac accumulates more slowly. The steady-state level of p53pac rises with decreasing oxygen concentration (Fig. 4B). Of note, we can compare the simulation results with the experimental observations in ref. 8; for comparison, the measured p53 expression level is divided by its maximum (see Supplemental Fig. S3). p53pac accumulates markedly only in severe hypoxia or anoxia, consistent with the experimental result, and the simulation results reproduce the key features of p53 dynamics in response to hypoxia.


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

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

Protein dynamics and apoptosis induction under severe hypoxia.(A–D) Color-coded concentrations of ATRp (A), p53pac (B), BIM (C) and PUMA (D) as a function of oxygen concentration and time. (E) The timing of Casp3 activation versus oxygen concentration. (F) Time courses of [Casp3] with oxygen concentration at 0.01% (green), 0.018% (blue), or 0.02% (red).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Protein dynamics and apoptosis induction under severe hypoxia.(A–D) Color-coded concentrations of ATRp (A), p53pac (B), BIM (C) and PUMA (D) as a function of oxygen concentration and time. (E) The timing of Casp3 activation versus oxygen concentration. (F) Time courses of [Casp3] with oxygen concentration at 0.01% (green), 0.018% (blue), or 0.02% (red).
Mentions: Under severe hypoxia, ATR is activated, and thus p53 is stabilized by phosphorylation. For oxygen concentration below 0.025%, [ATRp] quickly rises to plateau levels (Fig. 4A). ATR is partly activated when oxygen concentration is between 0.01% and 0.025%, or is fully activated when oxygen concentration is below 0.01%. Compared with ATRp, p53pac accumulates more slowly. The steady-state level of p53pac rises with decreasing oxygen concentration (Fig. 4B). Of note, we can compare the simulation results with the experimental observations in ref. 8; for comparison, the measured p53 expression level is divided by its maximum (see Supplemental Fig. S3). p53pac accumulates markedly only in severe hypoxia or anoxia, consistent with the experimental result, and the simulation results reproduce the key features of p53 dynamics in response to hypoxia.

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