RGD Reference Report - Estrogen-induced activation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor expression, and edema in the uterus are mediated by the phosphatidylinositol 3-kinase/Akt pathway. - Rat Genome Database

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Estrogen-induced activation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor expression, and edema in the uterus are mediated by the phosphatidylinositol 3-kinase/Akt pathway.

Authors: Kazi, Armina A  Koos, Robert D 
Citation: Kazi AA and Koos RD, Endocrinology. 2007 May;148(5):2363-74. doi: 10.1210/en.2006-1394. Epub 2007 Feb 1.
RGD ID: 152177689
Pubmed: PMID:17272396   (View Abstract at PubMed)
DOI: DOI:10.1210/en.2006-1394   (Journal Full-text)

Vascular endothelial growth factor (VEGF) plays an essential role in normal uterine physiology and function as well as endometrial cancer and other uterine disorders. Recently we showed that estrogen regulation of VEGF expression in the rat uterus involves rapid recruitment of both estrogen receptor (ER)-alpha and hypoxia-inducible factor (HIF)-1alpha to the VEGF promoter. Estrogen is known to stimulate both the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways, which have been linked to the activation of both of these transcription factors. Therefore, the involvement of these pathways in estrogen-induced VEGF expression was investigated. Inhibitors of the MAPK (U0126) or PI3K pathways (wortmannin or LY294002) were administered ip to immature female rats 1 h before 17beta-estradiol (E(2)) treatment. E(2) activation of both pathways occurred and was completely inhibited by the appropriate antagonist. Only PI3K inhibitors, however, blocked E(2) stimulation of VEGF mRNA expression and E(2)-induced uterine edema. In vivo chromatin immunoprecipitation analysis showed that this was associated with a failure of both HIF-1alpha and ERalpha to bind to the VEGF promoter. To determine whether inhibiting the PI3K pathway affected ERalpha induction of other estrogen target genes, the expression of creatine kinase B and progesterone receptor A/B was also examined. The expression of each was also inhibited by wortmannin, as was ERalpha binding to the creatine kinase B promoter. In conclusion, although estrogen activates both the MAPK and PI3K pathways in the rat uterus, activation of HIF-1alpha and ERalpha, and therefore regulation of VEGF gene expression is dependent only on the PI3K/Akt pathway. Furthermore, activation of the PI3K pathway appears to be a common requirement for the expression of estrogen-induced genes. These findings not only shed light on estrogen action in normal target tissues but also have important implications for cancer biology because excessive PI3K, HIF-1alpha, and VEGF activity are common in estrogen-dependent tumors.

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
estrogen increases phosphorylationISOAkt1 (Rattus norvegicus)152177689; 152177689estrogen increases phosphorylation of Akt1 protein] in rat uterusRGD 
estrogen increases phosphorylationEXP 152177689estrogen increases phosphorylation of Akt1 protein] in rat uterusRGD 
estrogen increases expression ISOCkb (Rattus norvegicus)152177689; 152177689estrogen increases expression of Ckb mRNA in rat uterusRGD 
estrogen increases expression EXP 152177689estrogen increases expression of Ckb mRNA in rat uterusRGD 
estrogen increases expression ISOEsr1 (Rattus norvegicus)152177689; 152177689estrogen increases expression of Esr1 mRNA in rat uterusRGD 
estrogen increases expression EXP 152177689estrogen increases expression of Esr1 mRNA in rat uterusRGD 
estrogen increases expression ISOHif1a (Rattus norvegicus)152177689; 152177689estrogen increases expression of Hif1a mRNA in rat uterusRGD 
estrogen increases expression EXP 152177689estrogen increases expression of Hif1a mRNA in rat uterusRGD 
estrogen increases phosphorylationISOMapk1 (Rattus norvegicus)152177689; 152177689estrogen increases phosphorylation of Mapk1/3 protein in rat uterusRGD 
estrogen increases phosphorylationISOMapk3 (Rattus norvegicus)152177689; 152177689estrogen increases phosphorylation of Mapk1/3 protein in rat uterusRGD 
estrogen increases phosphorylationEXP 152177689; 152177689estrogen increases phosphorylation of Mapk1/3 protein in rat uterusRGD 
estrogen increases expression ISOPgr (Rattus norvegicus)152177689; 152177689estrogen increases expression of Pgr mRNA in rat uterusRGD 
estrogen increases expression EXP 152177689estrogen increases expression of Pgr mRNA in rat uterusRGD 
estrogen increases expression ISOSp1 (Rattus norvegicus)152177689; 152177689estrogen increases expression of Sp1 mRNA in rat uterusRGD 
estrogen increases expression EXP 152177689estrogen increases expression of Sp1 mRNA in rat uterusRGD 
estrogen increases expression ISOVegfa (Rattus norvegicus)152177689; 152177689estrogen increases expression of Vegfa mRNA in rat uterusRGD 
estrogen increases expression EXP 152177689estrogen increases expression of Vegfa mRNA in rat uterusRGD 
LY294002 decreases reactionISOAkt1 (Rattus norvegicus)152177689; 152177689LY294002 inhibits the reaction [estrogen increases phosphorylation of Akt1 protein] in rat uterusRGD 
LY294002 decreases reactionEXP 152177689LY294002 inhibits the reaction [estrogen increases phosphorylation of Akt1 protein] in rat uterusRGD 
LY294002 decreases reactionISOHif1a (Rattus norvegicus)152177689; 152177689LY294002 inhibits the reaction [estrogen increases expression of Hif1a mRNA] in rat uterusRGD 
LY294002 decreases reactionEXP 152177689LY294002 inhibits the reaction [estrogen increases expression of Hif1a mRNA] in rat uterusRGD 
LY294002 decreases reactionISOVegfa (Rattus norvegicus)152177689; 152177689LY294002 inhibits the reaction [estrogen increases expression of Vegfa mRNA] in rat uterusRGD 
LY294002 decreases reactionEXP 152177689LY294002 inhibits the reaction [estrogen increases expression of Vegfa mRNA] in rat uterusRGD 
U0126 decreases reactionISOMapk1 (Rattus norvegicus)152177689; 152177689U0126 inhibits the reaction [estrogen increases phosphorylation of Mapk1/3 protein] in rat uterusRGD 
U0126 decreases reactionISOMapk3 (Rattus norvegicus)152177689; 152177689U0126 inhibits the reaction [estrogen increases phosphorylation of Mapk1/3 protein] in rat uterusRGD 
U0126 decreases reactionEXP 152177689; 152177689U0126 inhibits the reaction [estrogen increases phosphorylation of Mapk1/3 protein] in rat uterusRGD 
wortmannin decreases reactionISOAkt1 (Rattus norvegicus)152177689; 152177689wortmannin inhibits the reaction [estrogen increases phosphorylation of Akt1 protein] in rat uterusRGD 
wortmannin decreases reactionEXP 152177689wortmannin inhibits the reaction [estrogen increases phosphorylation of Akt1 protein] in rat uterusRGD 
wortmannin decreases reactionISOCkb (Rattus norvegicus)152177689; 152177689wortmannin inhibits the reaction [estrogen increases expression of Ckb mRNA] in rat uterusRGD 
wortmannin decreases reactionEXP 152177689wortmannin inhibits the reaction [estrogen increases expression of Ckb mRNA] in rat uterusRGD 
wortmannin decreases reactionISOEsr1 (Rattus norvegicus)152177689; 152177689wortmannin inhibits the reaction [estrogen increases expression of Esr1 mRNA] in rat uterusRGD 
wortmannin decreases reactionEXP 152177689wortmannin inhibits the reaction [estrogen increases expression of Esr1 mRNA] in rat uterusRGD 
wortmannin decreases reactionISOHif1a (Rattus norvegicus)152177689; 152177689wortmannin inhibits the reaction [estrogen increases expression of Hif1a mRNA] in rat uterusRGD 
wortmannin decreases reactionEXP 152177689wortmannin inhibits the reaction [estrogen increases expression of Hif1a mRNA] in rat uterusRGD 
wortmannin decreases reactionISOPgr (Rattus norvegicus)152177689; 152177689wortmannin inhibits the reaction [estrogen increases expression of Pgr mRNA] in rat uterusRGD 
wortmannin decreases reactionEXP 152177689wortmannin inhibits the reaction [estrogen increases expression of Pgr mRNA] in rat uterusRGD 
wortmannin decreases reactionISOSp1 (Rattus norvegicus)152177689; 152177689wortmannin inhibits the reaction [estrogen increases expression of Sp1 mRNA] in rat uterusRGD 
wortmannin decreases reactionEXP 152177689wortmannin inhibits the reaction [estrogen increases expression of Sp1 mRNA] in rat uterusRGD 
wortmannin decreases reactionISOVegfa (Rattus norvegicus)152177689; 152177689wortmannin inhibits the reaction [estrogen increases expression of Vegfa mRNA] in rat uterusRGD 
wortmannin decreases reactionEXP 152177689wortmannin inhibits the reaction [estrogen increases expression of Vegfa mRNA] in rat uterusRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Molecular Pathway Annotations    Click to see Annotation Detail View
Objects Annotated

Genes (Rattus norvegicus)
Akt1  (AKT serine/threonine kinase 1)
Ckb  (creatine kinase B)
Esr1  (estrogen receptor 1)
Hif1a  (hypoxia inducible factor 1 subunit alpha)
Mapk1  (mitogen activated protein kinase 1)
Mapk3  (mitogen activated protein kinase 3)
Pgr  (progesterone receptor)
Sp1  (Sp1 transcription factor)
Vegfa  (vascular endothelial growth factor A)

Genes (Mus musculus)
Akt1  (thymoma viral proto-oncogene 1)
Ckb  (creatine kinase, brain)
Esr1  (estrogen receptor 1 (alpha))
Hif1a  (hypoxia inducible factor 1, alpha subunit)
Mapk1  (mitogen-activated protein kinase 1)
Mapk3  (mitogen-activated protein kinase 3)
Pgr  (progesterone receptor)
Sp1  (trans-acting transcription factor 1)
Vegfa  (vascular endothelial growth factor A)

Genes (Homo sapiens)
AKT1  (AKT serine/threonine kinase 1)
CKB  (creatine kinase B)
ESR1  (estrogen receptor 1)
HIF1A  (hypoxia inducible factor 1 subunit alpha)
MAPK1  (mitogen-activated protein kinase 1)
MAPK3  (mitogen-activated protein kinase 3)
PGR  (progesterone receptor)
SP1  (Sp1 transcription factor)
VEGFA  (vascular endothelial growth factor A)


Additional Information