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

Anti-apoptotic action of nuclear ESR1 and ESR2

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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References:

1. Lee SY, Andoh T, Murphy DL, Chiueh CC
   17beta-estradiol activates ICI 182,780-sensitive estrogen receptors and cyclic GMP-dependent thioredoxin expression for neuroprotection. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 May;17(8):947-8
2. Chiueh C, Lee S, Andoh T, Murphy D
   Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. Endocrine 2003 Jun;21(1):27-31
3. Perillo B, Sasso A, Abbondanza C, Palumbo G
   17beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Molecular and cellular biology 2000 Apr;20(8):2890-901
4. Nilsen J, Chen S, Irwin RW, Iwamoto S, Brinton RD
   Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC neuroscience 2006 Nov 3;7:74
5. Wen Y, Perez EJ, Green PS, Sarkar SN, Simpkins JW
   nNOS is involved in estrogen mediated neuroprotection in neuroblastoma cells. Neuroreport 2004 Jun 28;15(9):1515-8
6. Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, Yodoi J
   Hemin-induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors. The Journal of biological chemistry 2001 May 25;276(21):18399-406
7. Andoh T, Chiueh CC, Chock PB
   Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. The Journal of biological chemistry 2003 Jan 10;278(2):885-90
8. Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, Cocito A, Amati B
   Genomic targets of the human c-Myc protein. Genes & development 2003 May 1;17(9):1115-29
9. Das KC, Lewis-Molock Y, White CW
   Elevation of manganese superoxide dismutase gene expression by thioredoxin. American journal of respiratory cell and molecular biology 1997 Dec;17(6):713-26
10. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H
    Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. The EMBO journal 1998 May 1;17(9):2596-606
11. Satoh M, Matter CM, Ogita H, Takeshita K, Wang CY, Dorn GW 2nd, Liao JK
    Inhibition of apoptosis-regulated signaling kinase-1 and prevention of congestive heart failure by estrogen. Circulation 2007 Jun 26;115(25):3197-204
12. Nishida K, Otsu K
    The role of apoptosis signal-regulating kinase 1 in cardiomyocyte apoptosis. Antioxidants & redox signaling 2006 Sep-Oct;8(9-10):1729-36