Estradiol exerts an anti-apoptotic effect on a wide variety of tissues that is mediated via activation of nuclear form of ESR1 (nuclear) and ESR2 [1], [2]. Under Estradiol action, ESR1 (nuclear) induces transcription of Bcl-2 [2], [3], [4].

Upon activation by Estradiol, ESR2 promotes anti-apoptotic action via induction of expression of nNOS and synthesis of NO, which leads to activation of Guanylate Cyclase 1, soluble, release of Cyclic GMP, and activation of Protein kinase cGMP-dependent (e.g., Protein kinase G1) [1], [2], [5]. Protein kinase G1 activates ERK1/2 possibly via c-Raf-1/ MEK1(MAP2K1) and MEK2(MAP2K2) pathway, and leads to activation of c-Myc and c-Jun transcription factors, which induce transcription of Thioredoxin (c-Jun acts as a part of c-Jun/c-Fos heterodimer) [6], [7], [8].

Thioredoxin binds to NF-kB1 (p50) and activates transcription of anti-apoptotic Bcl-2, which inhibits formation of mitochondrial permeability transition pore by Bax, and SOD2. This leads to decrease in mitochondrial Superoxide anion production during apoptosis [2], [7], [9].

Moreover, reduced form of Thioredoxin binds and inhibits pro-apoptotic kinase ASK1 (MAP3K5) [10], [11] which prevents activation of MEK3(MAP2K3), MEK4(MAP2K4), then p38alpha (MAPK14) and subsequently, JNK1(MAPK8) [12]. Thus, inhibited p38alpha (MAPK14) and JNK1(MAPK8) both cannot promote inhibition of Bcl-2, so it prevents formation of mitochondrial permeability transition pore by Bax and release of Cytochrome c from mitochondria [12].

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    Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. The EMBO journal 1998 May 1;17(9):2596-606
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