Limits...
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

Overview of the network dynamics under different hypoxic conditions.Temporal evolution of the levels of ATRp, p53pac, HIF-1αac, p21 and Casp3 in mild hypoxia (2% O2, (A)), severe hypoxia (0.02% O2, (B)), or anoxia (0% O2, (C)).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4561886&req=5

f2: Overview of the network dynamics under different hypoxic conditions.Temporal evolution of the levels of ATRp, p53pac, HIF-1αac, p21 and Casp3 in mild hypoxia (2% O2, (A)), severe hypoxia (0.02% O2, (B)), or anoxia (0% O2, (C)).

Mentions: To illustrate the typical dynamics of the HIF-1α and p53 pathways, we present the temporal evolution of protein concentrations under various hypoxic conditions in Fig. 2 ([…] denotes the concentration of each component throughout the paper). In mild hypoxia (2% O2), [p53pac] is at a basal level because ATR is inactivated, and thus Casp3 remains inactive (Fig. 2A). [HIF-1αac] gradually rises and drops to an intermediate level, since PHD is induced by HIF-1 to promote the degradation of HIF-1α (see Supplemental Fig. S1). p21 is induced by HIF-1 rather than p53 to trigger cell-cycle arrest. Consequently, the cell survives and adapts to mild hypoxia.


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

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

Overview of the network dynamics under different hypoxic conditions.Temporal evolution of the levels of ATRp, p53pac, HIF-1αac, p21 and Casp3 in mild hypoxia (2% O2, (A)), severe hypoxia (0.02% O2, (B)), or anoxia (0% O2, (C)).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Overview of the network dynamics under different hypoxic conditions.Temporal evolution of the levels of ATRp, p53pac, HIF-1αac, p21 and Casp3 in mild hypoxia (2% O2, (A)), severe hypoxia (0.02% O2, (B)), or anoxia (0% O2, (C)).
Mentions: To illustrate the typical dynamics of the HIF-1α and p53 pathways, we present the temporal evolution of protein concentrations under various hypoxic conditions in Fig. 2 ([…] denotes the concentration of each component throughout the paper). In mild hypoxia (2% O2), [p53pac] is at a basal level because ATR is inactivated, and thus Casp3 remains inactive (Fig. 2A). [HIF-1αac] gradually rises and drops to an intermediate level, since PHD is induced by HIF-1 to promote the degradation of HIF-1α (see Supplemental Fig. S1). p21 is induced by HIF-1 rather than p53 to trigger cell-cycle arrest. Consequently, the cell survives and adapts to mild 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