Anti-apoptotic action of membrane-bound ESR1
Estradiol exerts an anti-apoptotic effect on a wide variety of tissues. Estradiol as classical steroid hormone diffuses through plasma membrane, activates ESR1 (membrane) and promotes its membrane localization . Activation ESR1 (membrane) leads to anti-apoptosis , , .
Activated ESR1 (membrane) binds to and activates PI3K reg class IA (p85) , . PI3K cat class IA via PtdIns(3,4,5)P3 and PDK (PDPK1) activates AKT(PKB) . Upon Estradiol action, activated AKT(PKB) promotes anti-apoptosis.
Primarily, AKT(PKB) phosphorylates and activates eNOS which catalyzes the synthesis reaction of NO , . NO promotes cell survival by several mechanisms, including inhibition of mitochondrial permeability transition pore opening .
AKT(PKB) directly phosphorylates and activates CREB1, which regulates transcription of Bcl-2 , . . Also, AKT(PKB) phosphorylates and inhibits BAD, thus preventing its binding and inhibition of Bcl-2 and Bcl-XL .
As a result of Estradiol action AKT(PKB) inhibits ASK1 (MAP3K5)/ MEK4(MAP2K4)/ JNK(MAPK8-10) cascade preventing inhibition of Bcl-2 and Bcl-XL , , .
Activation of Bcl-2 and Bcl-XL and suppression of Bax under Estradiol action prevents formation of mitochondrial permeability transition pore, release of Cytochrome c from the mitochondria into the cytoplasm, and activation of caspase cascade , .
Estradiol can also activate Protein kinases C (PKC) (e.g., PKC-epsilon and/or PKC-alpha) , . This may be realized via PtdIns(3,4,5)P3  and PDK (PDPK1) , . PKC-epsilon and/or PKC-alpha phosphorylates voltage-dependent L-type Ca(II) channel, alpha 1C subunit and promotes Ca("2+) transport into the cytosol , . Intracellular Ca("2+) rise activates Ca-dependent conventional forms of PKC, possibly PKC-alpha, which activates c-Src/ c-Raf-1/ MEK1(MAP2K1) and MEK2(MAP2K2)/ ERK1/2 pathway , , . Activated ERK1/2 phosphorylates and activates p90RSK1 , , which activates CREB1, and that in turn promotes transcription of anti-apoptotic protein Bcl-2 , , . PKC-epsilon activated by Estradiol action also can directly bind to Bax and inhibit its translocation into mitochondria .
ESR1 (membrane) also can directly or through G-proteins signaling activate c-Src, which further leads to ERK1/2 and p90RSK1 p90RSK1 activation. Activated p90RSK1 directly inhibits BCL2-antagonist of cell death (BAD) , .
| AKT(PKB) || AKT(PKB) Protein group |
| ASK1 (MAP3K5) || Mitogen-activated protein kinase kinase kinase 5 |
| BAD || Bcl2 antagonist of cell death |
| Bax || Apoptosis regulator BAX |
| Bcl-2 || Apoptosis regulator Bcl-2 |
| Bcl-XL || Bcl-2-like protein 1 |
| CREB1 || Cyclic AMP-responsive element-binding protein 1 |
| Ca("2+) || Chemical IUPAC name calcium(+2) cation |
| Ca("2+) || Chemical IUPAC name calcium(+2) cation |
| Cytochrome c || Cytochrome c |
| ERK1/2 || Erk 1/2 Protein group |
| ESR1 (membrane) || Estrogen receptor |
| Estradiol || Chemical IUPAC name (8R,9S,13S,14S,17S)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol |
| JNK(MAPK8-10) || c-Jun N-terminal kinases Protein group |
| L-type Ca(II) channel, alpha 1C subunit || Voltage-dependent L-type calcium channel subunit alpha-1C |
| MEK1(MAP2K1) || Dual specificity mitogen-activated protein kinase kinase 1 |
| MEK2(MAP2K2) || Dual specificity mitogen-activated protein kinase kinase 2 |
| MEK4(MAP2K4) || Dual specificity mitogen-activated protein kinase kinase 4 |
| NO || Chemical IUPAC name Nitric oxide |
| PDK (PDPK1) || 3-phosphoinositide-dependent protein kinase 1 |
| PI3K cat class IA || The catalytic subunit of phosphatidylinositol 3-kinase subgroups IA Protein group |
| PI3K reg class IA (p85) || Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) Protein group |
| PKC-alpha || Protein kinase C alpha type |
| PKC-epsilon || Protein kinase C epsilon type |
| PtdIns(3,4,5)P3 || PtdIns(3,4,5)P3 Compound group |
| c-Raf-1 || RAF proto-oncogene serine/threonine-protein kinase |
| c-Src || Proto-oncogene tyrosine-protein kinase Src |
| eNOS || Nitric oxide synthase, endothelial |
| p90RSK1 || Ribosomal protein S6 kinase alpha-1 |
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