Pathway maps

Apoptosis and survival_Anti-apoptotic action of nuclear ESR1 and ESR2
Apoptosis and survival_Anti-apoptotic action of nuclear ESR1 and ESR2

Object List (links open in MetaCore):, MEK3 (MAP2K3), c-Myc, Nitric Oxide, SOD2, p38alpha (MAPK14), O(,2)('-), nNOS, Erk (MAPK1/3), Cytochrome c, Bcl-2, ESR2, H('+), ASK1 (MAP3K5), O(,2), c-Jun/c-Fos, MEK4 (MAP2K4),, c-Raf-1, H(,2)O(,2) cytoplasm, JNK1 (MAPK8), NF-kB p50/p65, Bax, Thioredoxin, (S)-citrulline, MEK1(MAP2K1), ESR1 (nuclear),, GTP, (L)-Arginine, c-Jun, Cyclic GMP cytosol, Protein kinase G1 alpha, Guanylate cyclase 1, soluble, Estradiol cytoplasm, MEK2(MAP2K2), NF-kB1 (p50)


Anti-apoptotic action of nuclear ESR1 and ESR2

17beta-estradiol exerts an anti-apoptotic effect on a wide variety of tissues that 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) induces transcription of B-cell CLL/lymphoma 2 ( Bcl-2) [3], [2], [4] .

Upon activation by 17beta-estradiol, ESR2 promotes anti-apoptotic action via induction of expression of Nitric oxide synthase 1 (neuronal) ( nNOS ) and synthesis 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 via V-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 ) pathway, and leads to activation of V-myc myelocytomatosis viral oncogene homolog ( c-Myc ) and Jun oncogene ( c-Jun ) transcription factors, which induce transcription of Thioredoxin ( c-Jun acts as a part of c-Jun/ V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) heterodimer) [6], [7], [8].

Thioredoxin binds to Nuclear factor of kappa light chain gene enhancer in B-cells 1 ( NF-kB1 (p50) ) and activates transcription of anti-apoptotic Bcl-2, which inhibits formation of mitochondrial permeability transition pore by BCL2-associated X protein ( Bax ), and Superoxide dismutase 2 mitochondrial ( SOD2 ). This leads to decrease in mitochondrial Superoxide anion production during apoptosis [9], [7], [2].

Moreover, reduced form of Thioredoxin binds and inhibits pro-apoptotic kinase ASK1 (MAP3K5) [10], [11] which prevents activation of Mitogen-activated protein kinase kinase 3 ( MEK3(MAP2K3) ), Mitogen-activated protein 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) 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].


  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