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Apoptosis and survival Anti-apoptotic action of nuclear ESR1 and ESR2


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Apoptosis and survival Anti-apoptotic action of nuclear ESR1 and ESR2

Anti-apoptotic action of nuclear ESR1 and ESR2

17beta-estradiol exerts an anti-apoptotic effect on a wide variety of tissuesthat is mediated via activation of nuclear form of Estrogen receptor 1 ( ESR1(nuclear) ) and Estrogen receptor 2 ( ESR2 ) [1], [2]. Under 17beta-estradiol action, ESR1 (nuclear) inducestranscription of B-cell CLL/lymphoma 2 ( Bcl-2) [3], [2], [4] .

Upon activation by 17beta-estradiol, ESR2 promotes anti-apoptotic action viainduction of expression of Nitric oxide synthase 1 (neuronal) ( nNOS ) andsynthesis of Nitric oxide, which leads to activation of Guanylate cyclase 1,soluble, release of CGMP, and activation of Protein kinase cGMP-dependent(e.g., Protein kinase G1 alpha ) [1], [2], [5]. Protein kinase G1 alpha activates Erk (MAPK1/3) possibly viaV-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activatedprotein kinase kinase 1 and 2 ( MEK1 and MEK2 ) pathway, and leads toactivation of V-myc myelocytomatosis viral oncogene homolog ( c-Myc ) and Junoncogene ( c-Jun ) transcription factors, which induce transcription ofThioredoxin ( c-Jun acts as a part of c-Jun/ V-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ) heterodimer) [6],[7], [8].

Thioredoxin binds to Nuclear factor of kappa light chain gene enhancer inB-cells 1 ( NF-kB1 (p50) ) and activates transcription of anti-apoptoticBcl-2, which inhibits formation of mitochondrial permeability transition pore byBCL2-associated X protein ( Bax ), and Superoxide dismutase 2 mitochondrial (SOD2 ). This leads to decrease in mitochondrial Superoxide anion production duringapoptosis [9], [7], [2].

Moreover, reduced form of Thioredoxin binds and inhibits pro-apoptotic kinaseASK1 (MAP3K5) [10], [11] which prevents activation ofMitogen-activated protein kinase kinase 3 ( MEK3(MAP2K3) ), Mitogen-activatedprotein kinase kinase 4 ( MEK4(MAP2K4) ), then Mitogen-activated protein kinase 14( p38alpha (MAPK14) ) and subsequently, Mitogen-activated protein kinase 8 (JNK1(MAPK8) ) [12]. Thus, inhibited p38alpha (MAPK14) andJNK1(MAPK8) both cannot promote inhibition of Bcl-2, so it preventsformation of mitochondrial permeability transition pore by Bax and release ofCytochrome C from mitochondria [12].