Pathway maps

Cell cycle_ESR1 regulation of G1/S transition
Cell cycle_ESR1 regulation of G1/S transition

Object List (links open in MetaCore):

SP1, c-Fos, c-Jun/c-Fos, ERK2 (MAPK1), CKS1, c-Myc, p21, CARM1, Estradiol cytoplasm, p130, Cullin 1, CRM1, E2F4, ATF-2/c-Jun, Ubiquitin, E2F4/DP1 complex, NCOA3 (pCIP/SRC3), E2F1, Cyclin D1, c-Jun, ESR1 (nuclear), Rb protein, SKP2, Skp2/TrCP/FBXW, Cyclin A, Cul1/Rbx1 E3 ligase, CDK6, CDK2, Cyclin E, E2F1/DP1 complex, CDK4, p27KIP1, CDC25A


ESR1 regulation of G1/S transition

17beta-estradiol induce s proliferation of estrogen receptor-positive cells. Estrogen receptor 1 ( ESR1 nuclear ) a ctivated by 17beta-estradiol acts like as ligand-dependent transcription factor and promotes G1/S transition 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 Jun oncogene ( c-Jun )/ V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [5], Activating transcription factor 2 ( 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 [10], [5].

Cyclin D1 binds and activates Cyclin-dependent kinases 4 and 6 ( CDK4 and CDK6 ), which regulate G1/S transition [11], [2]. Under 17beta-estradiol action, active Cyclin D1/ CDK4 and Cyclin D1/ CDK6 complexes phosphorylate Retinoblastoma 1 ( Rb-protein ). It leads to liberation of E2F/ transcription factor DP1 complexes ( E2F1/DP1, E2F4/DP1 ) 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. Coactivator-associated arginine methyltransferase 1 ( CARM1 ) in a Nuclear receptor coactivator 3 ( 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 is activation of transcription V-myc myelocytomatosis viral oncogene homolog ( c-Myc ) [15]. ESR1 nuclear induction of c-Myc leads activation of Cell division cycle 25 homolog A ( CDC25A ) and CDK4 transcription [16], [17]. Transcription of CDC25A is also regulated by E2F1 [18]. Active CDC25A dephosphorylates Cyclin-dependent kinase 2 ( CDK2 ). It leads to inhibition Rb protein and Retinoblastoma-like 2 ( p130 ) and transcription activation of E2F/DP1 -dependent S-phase genes, including Cyclin E gene [19], [20], [2].

In addition, ESR1 nuclear regulates G1/S transition by redistribution and down-regulation of Cyclin-dependent kinase inhibitor 1A ( p21 ) and Cyclin-dependent kinase inhibitor 1B ( 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 [21], [20].

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 SKP2 transcription by E2F1 [23]. c-Myc activates transcription of Cullin1 and Cyclin-dependent kinases regulatory subunit 1 ( CKS1 ) [24], [25]. CKS1 binds to SKP2 and promotes the recognition of phosphorylated p27KIP1 (on Thr187 by Cyclin E/ CDK2) [26], [25].

Finally, c-Myc can directly suppress transcription of p27KIP1 [27] and p21 under 17beta-estradiol action [28].

It is shown, that the membrane form of ESR1 participates in G1/S transition regulation as well. 17beta-estradiol down-regulates p27KIP1 by nuclear export via the ESR1 (membrane) / Mitogen-activated protein kinase 1( ERK2 )/ Exportin 1 ( CRM1 ) pathway [22], [29]. In addition, ESR1 (membrane) may stimulate Cyclin D1 through alternative pathways [30] [31]


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