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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

Schematic depiction of the model.The model characterizes crosstalk between the HIF-1 and p53 pathways upon hypoxia. In hypoxia, HIF-1α is stabilized due to reduced hydroxylation by PHD. Under severe hypoxia, the ATR kinase is activated via auto-phosphorylation upon hypoxia-induced replication arrest, and p53 is further activated by ATR. The shared coactivator p300 is required for the full transcriptional activity of p53 and HIF-1α. HIF-1α evokes transient cell-cycle arrest via inducing p21, whereas p53 can induce apoptosis via transrepressing or/and transactivating target genes. Dashed lines denote the expression of target genes by HIF-1α or p53, while solid arrowed lines represent the transitions between proteins. Circle- and bar-headed lines denote the promotion and inhibition of transition or production, respectively.
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f1: Schematic depiction of the model.The model characterizes crosstalk between the HIF-1 and p53 pathways upon hypoxia. In hypoxia, HIF-1α is stabilized due to reduced hydroxylation by PHD. Under severe hypoxia, the ATR kinase is activated via auto-phosphorylation upon hypoxia-induced replication arrest, and p53 is further activated by ATR. The shared coactivator p300 is required for the full transcriptional activity of p53 and HIF-1α. HIF-1α evokes transient cell-cycle arrest via inducing p21, whereas p53 can induce apoptosis via transrepressing or/and transactivating target genes. Dashed lines denote the expression of target genes by HIF-1α or p53, while solid arrowed lines represent the transitions between proteins. Circle- and bar-headed lines denote the promotion and inhibition of transition or production, respectively.

Mentions: Modeling crosstalk between the HIF-1 and p53 pathways. We constructed an integrated model to explore the cell-fate decision upon hypoxia, characterizing the activation of HIF-1α and p53, their selective expression of target genes, and apoptosis induction (Fig. 1). We focused on the interplay between HIF-1α and p53 under various hypoxic conditions. The key points of the model are presented as follows.


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

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

Schematic depiction of the model.The model characterizes crosstalk between the HIF-1 and p53 pathways upon hypoxia. In hypoxia, HIF-1α is stabilized due to reduced hydroxylation by PHD. Under severe hypoxia, the ATR kinase is activated via auto-phosphorylation upon hypoxia-induced replication arrest, and p53 is further activated by ATR. The shared coactivator p300 is required for the full transcriptional activity of p53 and HIF-1α. HIF-1α evokes transient cell-cycle arrest via inducing p21, whereas p53 can induce apoptosis via transrepressing or/and transactivating target genes. Dashed lines denote the expression of target genes by HIF-1α or p53, while solid arrowed lines represent the transitions between proteins. Circle- and bar-headed lines denote the promotion and inhibition of transition or production, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Schematic depiction of the model.The model characterizes crosstalk between the HIF-1 and p53 pathways upon hypoxia. In hypoxia, HIF-1α is stabilized due to reduced hydroxylation by PHD. Under severe hypoxia, the ATR kinase is activated via auto-phosphorylation upon hypoxia-induced replication arrest, and p53 is further activated by ATR. The shared coactivator p300 is required for the full transcriptional activity of p53 and HIF-1α. HIF-1α evokes transient cell-cycle arrest via inducing p21, whereas p53 can induce apoptosis via transrepressing or/and transactivating target genes. Dashed lines denote the expression of target genes by HIF-1α or p53, while solid arrowed lines represent the transitions between proteins. Circle- and bar-headed lines denote the promotion and inhibition of transition or production, respectively.
Mentions: Modeling crosstalk between the HIF-1 and p53 pathways. We constructed an integrated model to explore the cell-fate decision upon hypoxia, characterizing the activation of HIF-1α and p53, their selective expression of target genes, and apoptosis induction (Fig. 1). We focused on the interplay between HIF-1α and p53 under various hypoxic conditions. The key points of the model are presented as follows.

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