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].

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