Cell cycle - ESR1 regulation of G1/S transition

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ESR1 regulation of G1/S transition

Estradiol induces proliferation of estrogen receptor-positive cells. ESR1 (nuclear) activated by Estradiol acts like as ligand-dependent transcription factor and promotes G1/S transition (see G1/S transition of mitotic cell cycle) through several pathways [1], [2].

First, ESR1 (nuclear) activates transcription of Cyclin D1 by a variety mechanisms [3], [4], [5]. ESR1 (nuclear) can activate transcription of Cyclin D1 acting as co-activator c-Jun/ c-Fos [5], ATF-2/c-Jun heterodimers [3]. Moreover, ESR1 (nuclear) regulates transcription of c-Jun and c-Fos [6], [7]. In addition, ESR1 (nuclear) may activate transcription of Cyclin D1 via SP1-dependent pathways [8], [9]. Finally, Cyclin D1 can bind ESR1 (nuclear) and activate transcription of ESR1 (nuclear) -responsible genes including its own gene [5], [10].

Cyclin D1 binds and activates CDK4 and CDK6, which regulate G1/S transition of mitotic cell cycle [2], [11]. Under Estradiol action, active Cyclin D1/ CDK4 and Cyclin D1/ CDK6 complexes phosphorylate Rb protein. It leads to liberation of E2F1/DP1 complex, E2F4/DP1 complex) from inhibitory binding of Rb protein and transcription of requisite genes for S phase entry, including Cyclin E and Cyclin A genes [1], [2], [12].

Also, ESR1 (nuclear) can regulate transcription of E2F1. CARM1 in a NCOA3 (pCIP/SRC3) - dependent manner activates ligand-bound ESR1 (nuclear) which binds to SP1 and promotes transcription E2F1 [13], [14].

Another way of ESR1 (nuclear) promoting G1/S transition of mitotic cell cycle is activation of transcription of c-Myc [15]. ESR1 (nuclear) induction of c-Myc leads activation of CDC25A and CDK4 transcription [16], [17]. Transcription of CDC25A is also regulated by E2F1 [18]. Active CDC25A dephosphorylates CDK2. It leads to inhibition Rb protein and p130 and transcription activation of E2F/DP1-dependent S-phase genes, including Cyclin E gene [2], [19], [20].

In addition, ESR1 (nuclear) regulates G1/S transition by redistribution and down-regulation of p21 and p27KIP1. ESR1 (nuclear) promotes redistribution of p21 and p27KIP1 from Cyclin E / CDK2 to Cyclin D1/ CDKs. Thus the inhibitory activity of p21 and p27KIP1 removes from CDK2 [20], [21].

ESR1 (nuclear) may down-regulate p27KIP1 activity by targeting it for ubiquitin - proteosome degradation in nucleus [22]. ESR1 (nuclear) activation of E2F1 leads to activation of SKP2 transcription by E2F1 [23]. c-Myc activates transcription of Cullin 1 and CKS1 [24], [25]. CKS1 binds to SKP2 and promotes the recognition of phosphorylated p27KIP1 (on Thr187 by Cyclin E/ CDK2) [25], [26].

Finally, c-Myc can directly suppress transcription of p27KIP1 [27] and p21 under Estradiol action [28].

It is shown, that ESR1 (membrane) participates in regulation of G1/S transition of mitotic cell cycle as well. Estradiol down-regulates p27KIP1 by nuclear export via the ESR1 (membrane)/ ERK2 (MAPK1)/ CRM1 pathway [22], [29]. In addition, ESR1 (membrane) may stimulate Cyclin D1 through alternative pathways [30], [31].



Objects list:

ATF-2/c-Jun ATF-2/c-Jun Complex
CARM1 Histone-arginine methyltransferase CARM1
CDC25A M-phase inducer phosphatase 1
CDK2 Cyclin-dependent kinase 2
CDK4 Cyclin-dependent kinase 4
CDK6 Cyclin-dependent kinase 6
CKS1 Cyclin-dependent kinases regulatory subunit 1
CRM1 Exportin-1
Cullin 1 Cullin-1
Cyclin A Cyclin A Protein group
Cyclin D1 G1/S-specific cyclin-D1
Cyclin E G1/S-specific cyclin-E1
E2F1 Transcription factor E2F1
E2F1/DP1 complex E2F1/DP1 complex Complex
E2F4/DP1 complex E2F4/DP1 complex Complex
ERK2 (MAPK1) Mitogen-activated protein kinase 1
ESR1 (nuclear) 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
NCOA3 (pCIP/SRC3) Nuclear receptor coactivator 3
Rb protein Retinoblastoma-associated protein
SKP2 S-phase kinase-associated protein 2
SP1 Transcription factor Sp1
c-Fos Proto-oncogene c-Fos
c-Jun Transcription factor AP-1
c-Myc Myc proto-oncogene protein
p130 Retinoblastoma-like protein 2
p21 Cyclin-dependent kinase inhibitor 1
p27KIP1 Cyclin-dependent kinase inhibitor 1B

References:

  1. Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL
    Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. The Journal of biological chemistry 1997 Apr 18;272(16):10882-94
  2. Foster JS, Henley DC, Bukovsky A, Seth P, Wimalasena J
    Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Molecular and cellular biology 2001 Feb;21(3):794-810
  3. Sabbah M, Courilleau D, Mester J, Redeuilh G
    Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proceedings of the National Academy of Sciences of the United States of America 1999 Sep 28;96(20):11217-22
  4. Liu MM, Albanese C, Anderson CM, Hilty K, Webb P, Uht RM, Price RH Jr, Pestell RG, Kushner PJ
    Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. The Journal of biological chemistry 2002 Jul 5;277(27):24353-60
  5. Cicatiello L, Addeo R, Sasso A, Altucci L, Petrizzi VB, Borgo R, Cancemi M, Caporali S, Caristi S, Scafoglio C, Teti D, Bresciani F, Perillo B, Weisz A
    Estrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/estrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter. Molecular and cellular biology 2004 Aug;24(16):7260-74
  6. Weisz A, Rosales R
    Identification of an estrogen response element upstream of the human c-fos gene that binds the estrogen receptor and the AP-1 transcription factor. Nucleic acids research 1990 Sep 11;18(17):5097-106
  7. Hyder SM, Nawaz Z, Chiappetta C, Yokoyama K, Stancel GM
    The protooncogene c-jun contains an unusual estrogen-inducible enhancer within the coding sequence. The Journal of biological chemistry 1995 Apr 14;270(15):8506-13
  8. Wang W, Dong L, Saville B, Safe S
    Transcriptional activation of E2F1 gene expression by 17beta-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions. Molecular endocrinology (Baltimore, Md.) 1999 Aug;13(8):1373-87
  9. Safe S
    Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitamins and hormones 2001;62:231-52
  10. Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME
    Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Molecular and cellular biology 1997 Sep;17(9):5338-47
  11. Meyerson M, Harlow E
    Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Molecular and cellular biology 1994 Mar;14(3):2077-86
  12. Caldon CE, Daly RJ, Sutherland RL, Musgrove EA
    Cell cycle control in breast cancer cells. Journal of cellular biochemistry 2006 Feb 1;97(2):261-74
  13. Chen D, Huang SM, Stallcup MR
    Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300. The Journal of biological chemistry 2000 Dec 29;275(52):40810-6
  14. Frietze S, Lupien M, Silver PA, Brown M
    CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer research 2008 Jan 1;68(1):301-6
  15. Dubik D, Shiu RP
    Mechanism of estrogen activation of c-myc oncogene expression. Oncogene 1992 Aug;7(8):1587-94
  16. Galaktionov K, Chen X, Beach D
    Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 1996 Aug 8;382(6591):511-7
  17. Hermeking H, Rago C, Schuhmacher M, Li Q, Barrett JF, Obaya AJ, O'Connell BC, Mateyak MK, Tam W, Kohlhuber F, Dang CV, Sedivy JM, Eick D, Vogelstein B, Kinzler KW
    Identification of CDK4 as a target of c-MYC. Proceedings of the National Academy of Sciences of the United States of America 2000 Feb 29;97(5):2229-34
  18. Vigo E, Muller H, Prosperini E, Hateboer G, Cartwright P, Moroni MC, Helin K
    CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase. Molecular and cellular biology 1999 Sep;19(9):6379-95
  19. Lacy S, Whyte P
    Identification of a p130 domain mediating interactions with cyclin A/cdk 2 and cyclin E/cdk 2 complexes. Oncogene 1997 May 22;14(20):2395-406
  20. Prall OW, Rogan EM, Musgrove EA, Watts CK, Sutherland RL
    c-Myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Molecular and cellular biology 1998 Aug;18(8):4499-508
  21. Planas-Silva MD, Weinberg RA
    Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Molecular and cellular biology 1997 Jul;17(7):4059-69
  22. Foster JS, Fernando RI, Ishida N, Nakayama KI, Wimalasena J
    Estrogens down-regulate p27Kip1 in breast cancer cells through Skp2 and through nuclear export mediated by the ERK pathway. The Journal of biological chemistry 2003 Oct 17;278(42):41355-66
  23. Salon C, Merdzhanova G, Brambilla C, Brambilla E, Gazzeri S, Eymin B
    E2F-1, Skp2 and cyclin E oncoproteins are upregulated and directly correlated in high-grade neuroendocrine lung tumors. Oncogene 2007 Oct 18;26(48):6927-36
  24. O'Hagan RC, Ohh M, David G, de Alboran IM, Alt FW, Kaelin WG Jr, DePinho RA
    Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes & development 2000 Sep 1;14(17):2185-91
  25. Keller UB, Old JB, Dorsey FC, Nilsson JA, Nilsson L, MacLean KH, Chung L, Yang C, Spruck C, Boyd K, Reed SI, Cleveland JL
    Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis. The EMBO journal 2007 May 16;26(10):2562-74
  26. Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H
    p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Current biology : CB 1999 Jun 17;9(12):661-4
  27. Yang W, Shen J, Wu M, Arsura M, FitzGerald M, Suldan Z, Kim DW, Hofmann CS, Pianetti S, Romieu-Mourez R, Freedman LP, Sonenshein GE
    Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 2001 Mar 29;20(14):1688-702
  28. Mukherjee S, Conrad SE
    c-Myc suppresses p21WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells. The Journal of biological chemistry 2005 May 6;280(18):17617-25
  29. Castoria G, Migliaccio A, Di Domenico M, Lombardi M, de Falco A, Varricchio L, Bilancio A, Barone MV, Auricchio F
    Role of atypical protein kinase C in estradiol-triggered G1/S progression of MCF-7 cells. Molecular and cellular biology 2004 Sep;24(17):7643-53
  30. Cabodi S, Moro L, Baj G, Smeriglio M, Di Stefano P, Gippone S, Surico N, Silengo L, Turco E, Tarone G, Defilippi P
    p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen signaling in breast cancer cells. Journal of cell science 2004 Mar 15;117(Pt 8):1603-11
  31. Surmacz E, Bartucci M
    Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer. Journal of experimental & clinical cancer research : CR 2004 Sep;23(3):385-94

  1. Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL
    Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. The Journal of biological chemistry 1997 Apr 18;272(16):10882-94
  2. Foster JS, Henley DC, Bukovsky A, Seth P, Wimalasena J
    Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Molecular and cellular biology 2001 Feb;21(3):794-810
  3. Sabbah M, Courilleau D, Mester J, Redeuilh G
    Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proceedings of the National Academy of Sciences of the United States of America 1999 Sep 28;96(20):11217-22
  4. Liu MM, Albanese C, Anderson CM, Hilty K, Webb P, Uht RM, Price RH Jr, Pestell RG, Kushner PJ
    Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. The Journal of biological chemistry 2002 Jul 5;277(27):24353-60
  5. Cicatiello L, Addeo R, Sasso A, Altucci L, Petrizzi VB, Borgo R, Cancemi M, Caporali S, Caristi S, Scafoglio C, Teti D, Bresciani F, Perillo B, Weisz A
    Estrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/estrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter. Molecular and cellular biology 2004 Aug;24(16):7260-74
  6. Weisz A, Rosales R
    Identification of an estrogen response element upstream of the human c-fos gene that binds the estrogen receptor and the AP-1 transcription factor. Nucleic acids research 1990 Sep 11;18(17):5097-106
  7. Hyder SM, Nawaz Z, Chiappetta C, Yokoyama K, Stancel GM
    The protooncogene c-jun contains an unusual estrogen-inducible enhancer within the coding sequence. The Journal of biological chemistry 1995 Apr 14;270(15):8506-13
  8. Wang W, Dong L, Saville B, Safe S
    Transcriptional activation of E2F1 gene expression by 17beta-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions. Molecular endocrinology (Baltimore, Md.) 1999 Aug;13(8):1373-87
  9. Safe S
    Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitamins and hormones 2001;62:231-52
  10. Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME
    Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Molecular and cellular biology 1997 Sep;17(9):5338-47
  11. Meyerson M, Harlow E
    Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Molecular and cellular biology 1994 Mar;14(3):2077-86
  12. Caldon CE, Daly RJ, Sutherland RL, Musgrove EA
    Cell cycle control in breast cancer cells. Journal of cellular biochemistry 2006 Feb 1;97(2):261-74
  13. Chen D, Huang SM, Stallcup MR
    Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300. The Journal of biological chemistry 2000 Dec 29;275(52):40810-6
  14. Frietze S, Lupien M, Silver PA, Brown M
    CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer research 2008 Jan 1;68(1):301-6
  15. Dubik D, Shiu RP
    Mechanism of estrogen activation of c-myc oncogene expression. Oncogene 1992 Aug;7(8):1587-94
  16. Galaktionov K, Chen X, Beach D
    Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 1996 Aug 8;382(6591):511-7
  17. Hermeking H, Rago C, Schuhmacher M, Li Q, Barrett JF, Obaya AJ, O'Connell BC, Mateyak MK, Tam W, Kohlhuber F, Dang CV, Sedivy JM, Eick D, Vogelstein B, Kinzler KW
    Identification of CDK4 as a target of c-MYC. Proceedings of the National Academy of Sciences of the United States of America 2000 Feb 29;97(5):2229-34
  18. Vigo E, Muller H, Prosperini E, Hateboer G, Cartwright P, Moroni MC, Helin K
    CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase. Molecular and cellular biology 1999 Sep;19(9):6379-95
  19. Lacy S, Whyte P
    Identification of a p130 domain mediating interactions with cyclin A/cdk 2 and cyclin E/cdk 2 complexes. Oncogene 1997 May 22;14(20):2395-406
  20. Prall OW, Rogan EM, Musgrove EA, Watts CK, Sutherland RL
    c-Myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Molecular and cellular biology 1998 Aug;18(8):4499-508
  21. Planas-Silva MD, Weinberg RA
    Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Molecular and cellular biology 1997 Jul;17(7):4059-69
  22. Foster JS, Fernando RI, Ishida N, Nakayama KI, Wimalasena J
    Estrogens down-regulate p27Kip1 in breast cancer cells through Skp2 and through nuclear export mediated by the ERK pathway. The Journal of biological chemistry 2003 Oct 17;278(42):41355-66
  23. Salon C, Merdzhanova G, Brambilla C, Brambilla E, Gazzeri S, Eymin B
    E2F-1, Skp2 and cyclin E oncoproteins are upregulated and directly correlated in high-grade neuroendocrine lung tumors. Oncogene 2007 Oct 18;26(48):6927-36
  24. O'Hagan RC, Ohh M, David G, de Alboran IM, Alt FW, Kaelin WG Jr, DePinho RA
    Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes & development 2000 Sep 1;14(17):2185-91
  25. Keller UB, Old JB, Dorsey FC, Nilsson JA, Nilsson L, MacLean KH, Chung L, Yang C, Spruck C, Boyd K, Reed SI, Cleveland JL
    Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis. The EMBO journal 2007 May 16;26(10):2562-74
  26. Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H
    p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Current biology : CB 1999 Jun 17;9(12):661-4
  27. Yang W, Shen J, Wu M, Arsura M, FitzGerald M, Suldan Z, Kim DW, Hofmann CS, Pianetti S, Romieu-Mourez R, Freedman LP, Sonenshein GE
    Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 2001 Mar 29;20(14):1688-702
  28. Mukherjee S, Conrad SE
    c-Myc suppresses p21WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells. The Journal of biological chemistry 2005 May 6;280(18):17617-25
  29. Castoria G, Migliaccio A, Di Domenico M, Lombardi M, de Falco A, Varricchio L, Bilancio A, Barone MV, Auricchio F
    Role of atypical protein kinase C in estradiol-triggered G1/S progression of MCF-7 cells. Molecular and cellular biology 2004 Sep;24(17):7643-53
  30. Cabodi S, Moro L, Baj G, Smeriglio M, Di Stefano P, Gippone S, Surico N, Silengo L, Turco E, Tarone G, Defilippi P
    p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen signaling in breast cancer cells. Journal of cell science 2004 Mar 15;117(Pt 8):1603-11
  31. Surmacz E, Bartucci M
    Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer. Journal of experimental & clinical cancer research : CR 2004 Sep;23(3):385-94

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