Apoptosis and survival - Anti-apoptotic action of membrane-bound ESR1

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Anti-apoptotic action of membrane-bound ESR1

Estradiol exerts an anti-apoptotic effect on a wide variety of tissues. Estradiol as classical steroid hormone diffuses through plasma membrane, activates ESR1 (membrane) and promotes its membrane localization [1]. Activation ESR1 (membrane) leads to anti-apoptosis [2], [3], [4].

Activated ESR1 (membrane) binds to and activates PI3K reg class IA (p85) [5], [6]. PI3K cat class IA via PtdIns(3,4,5)P3 and PDK (PDPK1) activates AKT(PKB) [7]. Upon Estradiol action, activated AKT(PKB) promotes anti-apoptosis.

Primarily, AKT(PKB) phosphorylates and activates eNOS which catalyzes the synthesis reaction of NO [5], [8]. NO promotes cell survival by several mechanisms, including inhibition of mitochondrial permeability transition pore opening [9].

AKT(PKB) directly phosphorylates and activates CREB1, which regulates transcription of Bcl-2 [10], [3]. [11]. Also, AKT(PKB) phosphorylates and inhibits BAD, thus preventing its binding and inhibition of Bcl-2 and Bcl-XL [12].

As a result of Estradiol action AKT(PKB) inhibits ASK1 (MAP3K5)/ MEK4(MAP2K4)/ JNK(MAPK8-10) cascade preventing inhibition of Bcl-2 and Bcl-XL [13], [14], [15].

Activation of Bcl-2 and Bcl-XL and suppression of Bax under Estradiol action prevents formation of mitochondrial permeability transition pore, release of Cytochrome c from the mitochondria into the cytoplasm, and activation of caspase cascade [12], [16].

Estradiol can also activate Protein kinases C (PKC) (e.g., PKC-epsilon and/or PKC-alpha) [17], [18]. This may be realized via PtdIns(3,4,5)P3 [19] and PDK (PDPK1) [20], [21]. PKC-epsilon and/or PKC-alpha phosphorylates voltage-dependent L-type Ca(II) channel, alpha 1C subunit and promotes Ca('2+) transport into the cytosol [17], [22]. Intracellular Ca('2+) rise activates Ca-dependent conventional forms of PKC, possibly PKC-alpha, which activates c-Src/ c-Raf-1/ MEK1(MAP2K1) and MEK2(MAP2K2)/ ERK1/2 pathway [23], [24], [25]. Activated ERK1/2 phosphorylates and activates p90RSK1 [26], [27], which activates CREB1, and that in turn promotes transcription of anti-apoptotic protein Bcl-2 [12], [22], [28]. PKC-epsilon activated by Estradiol action also can directly bind to Bax and inhibit its translocation into mitochondria [29].

ESR1 (membrane) also can directly or through G-proteins signaling activate c-Src, which further leads to ERK1/2 and p90RSK1 p90RSK1 activation. Activated p90RSK1 directly inhibits BCL2-antagonist of cell death (BAD) [26], [27].



Objects list:

AKT(PKB) AKT(PKB) Protein group
ASK1 (MAP3K5) Mitogen-activated protein kinase kinase kinase 5
BAD Bcl2 antagonist of cell death
Bax Apoptosis regulator BAX
Bcl-2 Apoptosis regulator Bcl-2
Bcl-XL Bcl-2-like protein 1
CREB1 Cyclic AMP-responsive element-binding protein 1
Ca('2+) Chemical IUPAC name calcium(+2) cation
Ca('2+) Chemical IUPAC name calcium(+2) cation
Cytochrome c Cytochrome c
ERK1/2 Erk 1/2 Protein group
ESR1 (membrane) Estrogen receptor
Estradiol Chemical IUPAC name (8R,9S,13S,14S,17S)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol
JNK(MAPK8-10) c-Jun N-terminal kinases Protein group
L-type Ca(II) channel, alpha 1C subunit Voltage-dependent L-type calcium channel subunit alpha-1C
MEK1(MAP2K1) Dual specificity mitogen-activated protein kinase kinase 1
MEK2(MAP2K2) Dual specificity mitogen-activated protein kinase kinase 2
MEK4(MAP2K4) Dual specificity mitogen-activated protein kinase kinase 4
NO Chemical IUPAC name Nitric oxide
PDK (PDPK1) 3-phosphoinositide-dependent protein kinase 1
PI3K cat class IA The catalytic subunit of phosphatidylinositol 3-kinase subgroups IA Protein group
PI3K reg class IA (p85) Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) Protein group
PKC-alpha Protein kinase C alpha type
PKC-epsilon Protein kinase C epsilon type
PtdIns(3,4,5)P3 PtdIns(3,4,5)P3 Compound group
c-Raf-1 RAF proto-oncogene serine/threonine-protein kinase
c-Src Proto-oncogene tyrosine-protein kinase Src
eNOS Nitric oxide synthase, endothelial
p90RSK1 Ribosomal protein S6 kinase alpha-1

References:

  1. Prossnitz ER, Arterburn JB, Sklar LA
    GPR30: A G protein-coupled receptor for estrogen. Molecular and cellular endocrinology 2007 Feb;265-266:138-42
  2. Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC
    Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001 Mar 9;104(5):719-30
  3. Honda K, Shimohama S, Sawada H, Kihara T, Nakamizo T, Shibasaki H, Akaike A
    Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. Journal of neuroscience research 2001 Jun 1;64(5):466-75
  4. Wang M, Crisostomo P, Wairiuko GM, Meldrum DR
    Estrogen receptor-alpha mediates acute myocardial protection in females. American journal of physiology. Heart and circulatory physiology 2006 Jun;290(6):H2204-9
  5. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK
    Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000 Sep 28;407(6803):538-41
  6. Mannella P, Brinton RD
    Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. The Journal of neuroscience : the official journal of the Society for Neuroscience 2006 Sep 13;26(37):9439-47
  7. Scheid MP, Woodgett JR
    Unravelling the activation mechanisms of protein kinase B/Akt. FEBS letters 2003 Jul 3;546(1):108-12
  8. Mendelsohn ME
    Nongenomic, ER-mediated activation of endothelial nitric oxide synthase: how does it work? What does it mean? Circulation research 2000 Nov 24;87(11):956-60
  9. Murphy E, Steenbergen C
    Cardioprotection in females: a role for nitric oxide and altered gene expression. Heart failure reviews 2007 Dec;12(3-4):293-300
  10. Du K, Montminy M
    CREB is a regulatory target for the protein kinase Akt/PKB. The Journal of biological chemistry 1998 Dec 4;273(49):32377-9
  11. Brunet A, Datta SR, Greenberg ME
    Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Current opinion in neurobiology 2001 Jun;11(3):297-305
  12. Nilsen J, Brinton RD
    Mitochondria as therapeutic targets of estrogen action in the central nervous system. Current drug targets. CNS and neurological disorders 2004 Aug;3(4):297-313
  13. Razandi M, Pedram A, Levin ER
    Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Molecular endocrinology (Baltimore, Md.) 2000 Sep;14(9):1434-47
  14. Eckhoff DE, Smyth CA, Eckstein C, Bilbao G, Young CJ, Thompson JA, Contreras JL
    Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction. Surgery 2003 Aug;134(2):169-79
  15. Mabuchi S, Ohmichi M, Kimura A, Nishio Y, Arimoto-Ishida E, Yada-Hashimoto N, Tasaka K, Murata Y
    Estrogen inhibits paclitaxel-induced apoptosis via the phosphorylation of apoptosis signal-regulating kinase 1 in human ovarian cancer cell lines. Endocrinology 2004 Jan;145(1):49-58
  16. 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
  17. Yang L, Liu G, Zakharov SI, Morrow JP, Rybin VO, Steinberg SF, Marx SO
    Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms. The Journal of biological chemistry 2005 Jan 7;280(1):207-14
  18. Sovershaev MA, Egorina EM, Andreasen TV, Jonassen AK, Ytrehus K
    Preconditioning by 17beta-estradiol in isolated rat heart depends on PI3-K/PKB pathway, PKC, and ROS. American journal of physiology. Heart and circulatory physiology 2006 Oct;291(4):H1554-62
  19. Toker A, Meyer M, Reddy KK, Falck JR, Aneja R, Aneja S, Parra A, Burns DJ, Ballas LM, Cantley LC
    Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. The Journal of biological chemistry 1994 Dec 23;269(51):32358-67
  20. Dutil EM, Toker A, Newton AC
    Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Current biology : CB 1998 Dec 17-31;8(25):1366-75
  21. Cenni V, Doppler H, Sonnenburg ED, Maraldi N, Newton AC, Toker A
    Regulation of novel protein kinase C epsilon by phosphorylation. The Biochemical journal 2002 May 1;363(Pt 3):537-45
  22. Wu TW, Wang JM, Chen S, Brinton RD
    17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neuroprotection. Neuroscience 2005;135(1):59-72
  23. Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR
    Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature 1993 Jul 15;364(6434):249-52
  24. Schonwasser DC, Marais RM, Marshall CJ, Parker PJ
    Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Molecular and cellular biology 1998 Feb;18(2):790-8
  25. Cordey M, Gundimeda U, Gopalakrishna R, Pike CJ
    Estrogen activates protein kinase C in neurons: role in neuroprotection. Journal of neurochemistry 2003 Mar;84(6):1340-8
  26. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME
    Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science (New York, N.Y.) 1999 Nov 12;286(5443):1358-62
  27. Fernando RI, Wimalasena J
    Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt. Molecular biology of the cell 2004 Jul;15(7):3266-84
  28. Subramanian M, Shaha C
    Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. Journal of immunology (Baltimore, Md. : 1950) 2007 Aug 15;179(4):2330-8
  29. Lu D, Sivaprasad U, Huang J, Shankar E, Morrow S, Basu A
    Protein kinase C-epsilon protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation. Apoptosis : an international journal on programmed cell death 2007 Oct;12(10):1893-900

  1. Prossnitz ER, Arterburn JB, Sklar LA
    GPR30: A G protein-coupled receptor for estrogen. Molecular and cellular endocrinology 2007 Feb;265-266:138-42
  2. Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC
    Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001 Mar 9;104(5):719-30
  3. Honda K, Shimohama S, Sawada H, Kihara T, Nakamizo T, Shibasaki H, Akaike A
    Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. Journal of neuroscience research 2001 Jun 1;64(5):466-75
  4. Wang M, Crisostomo P, Wairiuko GM, Meldrum DR
    Estrogen receptor-alpha mediates acute myocardial protection in females. American journal of physiology. Heart and circulatory physiology 2006 Jun;290(6):H2204-9
  5. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK
    Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000 Sep 28;407(6803):538-41
  6. Mannella P, Brinton RD
    Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. The Journal of neuroscience : the official journal of the Society for Neuroscience 2006 Sep 13;26(37):9439-47
  7. Scheid MP, Woodgett JR
    Unravelling the activation mechanisms of protein kinase B/Akt. FEBS letters 2003 Jul 3;546(1):108-12
  8. Mendelsohn ME
    Nongenomic, ER-mediated activation of endothelial nitric oxide synthase: how does it work? What does it mean? Circulation research 2000 Nov 24;87(11):956-60
  9. Murphy E, Steenbergen C
    Cardioprotection in females: a role for nitric oxide and altered gene expression. Heart failure reviews 2007 Dec;12(3-4):293-300
  10. Du K, Montminy M
    CREB is a regulatory target for the protein kinase Akt/PKB. The Journal of biological chemistry 1998 Dec 4;273(49):32377-9
  11. Brunet A, Datta SR, Greenberg ME
    Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Current opinion in neurobiology 2001 Jun;11(3):297-305
  12. Nilsen J, Brinton RD
    Mitochondria as therapeutic targets of estrogen action in the central nervous system. Current drug targets. CNS and neurological disorders 2004 Aug;3(4):297-313
  13. Razandi M, Pedram A, Levin ER
    Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Molecular endocrinology (Baltimore, Md.) 2000 Sep;14(9):1434-47
  14. Eckhoff DE, Smyth CA, Eckstein C, Bilbao G, Young CJ, Thompson JA, Contreras JL
    Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction. Surgery 2003 Aug;134(2):169-79
  15. Mabuchi S, Ohmichi M, Kimura A, Nishio Y, Arimoto-Ishida E, Yada-Hashimoto N, Tasaka K, Murata Y
    Estrogen inhibits paclitaxel-induced apoptosis via the phosphorylation of apoptosis signal-regulating kinase 1 in human ovarian cancer cell lines. Endocrinology 2004 Jan;145(1):49-58
  16. 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
  17. Yang L, Liu G, Zakharov SI, Morrow JP, Rybin VO, Steinberg SF, Marx SO
    Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms. The Journal of biological chemistry 2005 Jan 7;280(1):207-14
  18. Sovershaev MA, Egorina EM, Andreasen TV, Jonassen AK, Ytrehus K
    Preconditioning by 17beta-estradiol in isolated rat heart depends on PI3-K/PKB pathway, PKC, and ROS. American journal of physiology. Heart and circulatory physiology 2006 Oct;291(4):H1554-62
  19. Toker A, Meyer M, Reddy KK, Falck JR, Aneja R, Aneja S, Parra A, Burns DJ, Ballas LM, Cantley LC
    Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. The Journal of biological chemistry 1994 Dec 23;269(51):32358-67
  20. Dutil EM, Toker A, Newton AC
    Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Current biology : CB 1998 Dec 17-31;8(25):1366-75
  21. Cenni V, Doppler H, Sonnenburg ED, Maraldi N, Newton AC, Toker A
    Regulation of novel protein kinase C epsilon by phosphorylation. The Biochemical journal 2002 May 1;363(Pt 3):537-45
  22. Wu TW, Wang JM, Chen S, Brinton RD
    17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neuroprotection. Neuroscience 2005;135(1):59-72
  23. Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR
    Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature 1993 Jul 15;364(6434):249-52
  24. Schonwasser DC, Marais RM, Marshall CJ, Parker PJ
    Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Molecular and cellular biology 1998 Feb;18(2):790-8
  25. Cordey M, Gundimeda U, Gopalakrishna R, Pike CJ
    Estrogen activates protein kinase C in neurons: role in neuroprotection. Journal of neurochemistry 2003 Mar;84(6):1340-8
  26. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME
    Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science (New York, N.Y.) 1999 Nov 12;286(5443):1358-62
  27. Fernando RI, Wimalasena J
    Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt. Molecular biology of the cell 2004 Jul;15(7):3266-84
  28. Subramanian M, Shaha C
    Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. Journal of immunology (Baltimore, Md. : 1950) 2007 Aug 15;179(4):2330-8
  29. Lu D, Sivaprasad U, Huang J, Shankar E, Morrow S, Basu A
    Protein kinase C-epsilon protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation. Apoptosis : an international journal on programmed cell death 2007 Oct;12(10):1893-900

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