Apoptosis and survival Anti-apoptotic action of membrane-bound ESR1
Anti-apoptotic action of membrane-bound ESR1 17beta-estradiol exerts an anti-apoptotic effect on a wide variety of tissuesthat is mediated via activation of membrane bound Estrogen receptor 1 (ESR1(membrane) ), which activates several anti-apoptotic pathways , , . Activated ESR1(membrane) binds to and activates Phosphoinositide-3-kinase (PI3K ) , . PI3K via Phosphatidylinositol(3,4,5) trisphosphate ( PtdIns(3,4,5)P3 ) and 3-phosphoinositide dependent proteinkinase-1 ( PDK(PDPK1) ) activates V-akt murine thymoma viral oncogene homologs (AKT(PKB) ) . Upon 17beta-estradiol action, activatedAKT(PKB) promotes several anti-apoptotic pathways. Primarily, AKT(PKB) phosphorylates and activates Nitric oxide synthase 3 (eNOS ) which catalyzes the synthesis reaction of Nitric oxide , . Nitric oxide promotes cell survival by severalmechanisms, including inhibition of mitochondrial permeability transition pore opening. AKT(PKB) directly phosphorylates and activates CREB1, which regulatestranscription of Bcl-2 , . . Also,AKT(PKB) phosphorylates and inhibits BAD, thus preventing its binding andinhibition of Bcl-2 and Bcl-XL . As a result of 17beta-estradiol action AKT(PKB) inhibitsMitogen-activated protein kinase kinase kinase 5 ( ASK1 (MAP3K5) )/Mitogen-activated protein kinase kinase 4 ( MEK4(MAP2K4) )/ Mitogen-activatedprotein kinases 8-10 ( JNK (MAPK8-10) cascade preventing inhibition ofBcl-2 and Bcl-XL , , . Activation of Bcl-2 and Bcl-XL and suppression of Bax under17beta-estradiol action prevents formation of mitochondrial permeabilitytransition pore, release of Cytochrome C from the mitochondria into the cytoplasm,and activation of caspase cascade , . 17beta-estradiol can also activate Protein kinases C (PKC) (e.g.,PKC-epsilon and/or PKC-alpha ) , . This maybe realized via PtdIns(3,4,5)P3  and PDK(PDPK1) , . PKC-epsilon and/or PKC-alpha phosphorylatesvoltage-dependent Calcium channel L type alpha 1C subunit ( L-type Ca(II) channel,alpha 1C subunit ) and promotes Ca('2+) transport into the cytosol , . Intracellular Ca('2+) rise activates Ca-dependentconventional forms of PKC, possibly PKC-alpha, which activates V-src sarcomaviral oncogene homolog ( c-Src )/ V-raf-1 murine leukemia viral oncogene homolog1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 andMEK2 )/ Mitogen-activated protein kinases 1 and 3 ( Erk(MAPK1/3) ) pathway, , . Activated Erk(MAPK1/3)phosphorylates and activates Ribosomal protein S6 kinase 90kDa polypeptide 1 (p90RSK1 ) , , which activates cAMP responsiveelement binding protein 1 ( CREB1 ), and that in turn promotes transcription ofanti-apoptotic protein B-cell CLL/lymphoma 2 ( Bcl-2 ) , , . PKC-epsilon activated by 17beta-estradiolaction also can directly bind to BCL2-associated X protein ( Bax ) and inhibit itstranslocation into mitochondria . ESR1 (membrane) also can directly or through G-proteins signaling activatec-Src, which further leads to Erk(MAPK1/3) and p90RSK2 (RPS6KA3)activation. Activated p90RSK1 directly inhibits BCL2-antagonist of cell death (BAD ) , .