An essential role for p300/CBP in the cellular response to hypoxia

Arany, Zoltàn; Huang, L. Eric; Eckner, Richard; Bhattacharya, Shoumo; Jiang, Chian; Goldberg, Mark A.; Bunn, H. Franklin; Livingston, David M.

doi:10.1073/pnas.93.23.12969

Cited by 727 publications

(513 citation statements)

References 41 publications

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“…However, the NAD and CAD of human HIF-1a share little amino-acid similarity with each other, implying divergent yet highly important roles for each domain. 17 Both the NAD and CAD employ recruitment of the coactivators CBP/p300, SRC-1, and transcription intermediary factor 2 (TIF-2), [18][19][20] although direct interactions have only been demonstrated between the CAD and p300 or Crebbinding protein (CBP). 21 CBP and p300 are paralogous transcriptional coactivators that are essential for linking HIF and other transcription factors with coactivator complexes and the basal transcriptional machinery, and are thus indispensable for robust transcriptional activation.…”

Section: Hif Transactivation Domainsmentioning

confidence: 99%

Turn me on: regulating HIF transcriptional activity

2008

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The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

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Section: Hif Transactivation Domainsmentioning

confidence: 99%

Turn me on: regulating HIF transcriptional activity

2008

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“…HIF-1 consists of an oxygensensitive a subunit, which determines the activity of HIF-1, and a b subunit, which is constitutively expressed. During hypoxia, HIF-1a is stabilized and forms a dimer with HIF-1b and then binds to the hypoxia response element (HRE) in HIF-1 target genes with other transcription factors, such as p300/CBP (Arany et al, 1996). The stability and activity of HIF-1a are regulated by post-translational modifications, such as hydroxylation, acetylation, ubiquitination and phosphorylation (Ravi et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

et al. 2011

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Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1a. Mel-18 negatively regulated the HIF-1a expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1a expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1a protein level. Mel-18 modulated the HIF-1a transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1a/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1a expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1a and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.

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“…Activation of the HIF transcription pathway induces the expression of over a hundred genes, which encode proteins involved in the regulation of glucose metabolism, cell migration, and neovascularization. 5,6 HIF-1α overexpression is a common occurrence in most human cancers and has been associated with drug resistance mechanisms. 2,7−10 Thus, because of the central role of HIF in cancer, it has become an important target for cancer therapy using different approaches.…”

mentioning

confidence: 99%

Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor

Shi

Yin

Kaluz

et al. 2012

ACS Med. Chem. Lett.

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Hypoxia inducible factors (HIFs) are transcription factors that activate expression of multiple gene products and promote tumor adaptation to a hypoxic environment. To become transcriptionally active, HIFs associate with cofactors p300 or CBP. Previously, we found that arylsulfonamides can antagonize HIF transcription in a bioassay, block the p300/HIF-1α interaction, and exert potent anticancer activity in several animal models. In the present work, KCN1-bead affinity pull down, 14 Clabeled KCN1 binding, and KCN1-surface plasmon resonance measurements provide initial support for a mechanism in which KCN1 can bind to the CH1 domain of p300 and likely prevent the p300/HIF-1α assembly. Using a previously reported NMR structure of the p300/HIF-1α complex, we have identified potential binding sites in the p300-CH1 domain. A two-site binding model coupled with IC 50 values has allowed establishment of a modest ROC-based enrichment and creation of a guide for future analogue synthesis.

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An essential role for p300/CBP in the cellular response to hypoxia

Cited by 727 publications

References 41 publications

Turn me on: regulating HIF transcriptional activity

Turn me on: regulating HIF transcriptional activity

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor

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