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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

Effect of miR-17-92 on apoptosis induction under severe hypoxia (0.02% O2).(A) Bifurcation diagrams of [PTEN] (green), [BIM] (red) and [miR-17-92] (blue) as a function of jsmir. (B–F) Time courses of [p53pac] (B), [PTEN] (C), [BIM] (D), [PUMA] (E) and [Casp3] (F) with jsmir = 0.3 (blue), 0.8 (red), or 2.0 (green).
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f6: Effect of miR-17-92 on apoptosis induction under severe hypoxia (0.02% O2).(A) Bifurcation diagrams of [PTEN] (green), [BIM] (red) and [miR-17-92] (blue) as a function of jsmir. (B–F) Time courses of [p53pac] (B), [PTEN] (C), [BIM] (D), [PUMA] (E) and [Casp3] (F) with jsmir = 0.3 (blue), 0.8 (red), or 2.0 (green).

Mentions: As shown in the bifurcation diagrams, [PTEN] and [BIM] remain at relatively high levels for jsmir  ≤ 1, whereas [miR-17-92] is at low levels (Fig. 6A). In contrast, [PTEN] and [BIM] stay at low levels once jsmir > 1, whereas [miR-17-92] gradually rises with increasing jsmir. This suggests that the effective transrepression of miR-17-92 by p53 is indispensable for apoptosis induction under severe hypoxia, which awaits experimental validation.


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

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

Effect of miR-17-92 on apoptosis induction under severe hypoxia (0.02% O2).(A) Bifurcation diagrams of [PTEN] (green), [BIM] (red) and [miR-17-92] (blue) as a function of jsmir. (B–F) Time courses of [p53pac] (B), [PTEN] (C), [BIM] (D), [PUMA] (E) and [Casp3] (F) with jsmir = 0.3 (blue), 0.8 (red), or 2.0 (green).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Effect of miR-17-92 on apoptosis induction under severe hypoxia (0.02% O2).(A) Bifurcation diagrams of [PTEN] (green), [BIM] (red) and [miR-17-92] (blue) as a function of jsmir. (B–F) Time courses of [p53pac] (B), [PTEN] (C), [BIM] (D), [PUMA] (E) and [Casp3] (F) with jsmir = 0.3 (blue), 0.8 (red), or 2.0 (green).
Mentions: As shown in the bifurcation diagrams, [PTEN] and [BIM] remain at relatively high levels for jsmir  ≤ 1, whereas [miR-17-92] is at low levels (Fig. 6A). In contrast, [PTEN] and [BIM] stay at low levels once jsmir > 1, whereas [miR-17-92] gradually rises with increasing jsmir. This suggests that the effective transrepression of miR-17-92 by p53 is indispensable for apoptosis induction under severe hypoxia, which awaits experimental validation.

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