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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

Dynamics of HIF-1αac and p21.Color-coded concentrations of (A) HIF-1αac and (B) p21 as a function of the logarithm of oxygen concentration and time.
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f3: Dynamics of HIF-1αac and p21.Color-coded concentrations of (A) HIF-1αac and (B) p21 as a function of the logarithm of oxygen concentration and time.

Mentions: To investigate the dynamics of HIF-1α and p21 systematically, we plot the heat maps of [HIF-1αac] and [p21] as a function of oxygen concentration and time (Fig. 3). In normoxia (above 3% O2), [HIF-1αac] remains at basal levels since most of HIF-1α is degraded (Fig. 3A). In mild hypoxia (between 1.1% and 3% O2), [HIF-1αac] gradually rises and drops due to PHD-dependent degradation. In moderate hypoxia (between 0.03% and 1.1% O2), [HIF-1αac] rises to different plateau levels, which can be as high as 1.6. p21 dynamics closely follow the dynamics of HIF-1αac (Fig. 3B). These results suggest that the cell undergoes a transient cell-cycle arrest in mild hypoxia, or becomes senescent under moderate hypoxia because of sustained p21 induction. It would be interesting to test the occurrence of senescence.


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

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

Dynamics of HIF-1αac and p21.Color-coded concentrations of (A) HIF-1αac and (B) p21 as a function of the logarithm of oxygen concentration and time.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Dynamics of HIF-1αac and p21.Color-coded concentrations of (A) HIF-1αac and (B) p21 as a function of the logarithm of oxygen concentration and time.
Mentions: To investigate the dynamics of HIF-1α and p21 systematically, we plot the heat maps of [HIF-1αac] and [p21] as a function of oxygen concentration and time (Fig. 3). In normoxia (above 3% O2), [HIF-1αac] remains at basal levels since most of HIF-1α is degraded (Fig. 3A). In mild hypoxia (between 1.1% and 3% O2), [HIF-1αac] gradually rises and drops due to PHD-dependent degradation. In moderate hypoxia (between 0.03% and 1.1% O2), [HIF-1αac] rises to different plateau levels, which can be as high as 1.6. p21 dynamics closely follow the dynamics of HIF-1αac (Fig. 3B). These results suggest that the cell undergoes a transient cell-cycle arrest in mild hypoxia, or becomes senescent under moderate hypoxia because of sustained p21 induction. It would be interesting to test the occurrence of senescence.

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