Reproduction - Progesterone-mediated oocyte maturation

Progesterone-mediated oocyte maturation

In growing follicles oocytes remain arrested at the I meiotic prophase. For the most vertebrates the maturation process extends up to the II meiotic arrest when the oocytes are ready for fertilization. Failure of the oocyte ovulation results in luteinizing hormone-stimulated progesterone production by follicular cells surrounding the oocyte. Progesterone is considered to be the physiological stimulus for the meiosis resumption [1], [2].

The meiosis reinitiation depends on the activation of maturation-promoting factor (MPF) - the complex consisted of Cell division cycle 2 kinase (CDK1 (p34)) and Cyclin B1 [1]. MPF is maintained in its inactive state by phosphorylation of CDK1 (p34) by Membrane associated tyrosine/threonine 1(Myt1) [3] and WEE1 homolog 2(Wee1B) protein kinases [4]. The MPF is activated through the CDK1 (p34) dephosphorylation by the members of the Cdc25 phosphatase family [5]: Cell division cycle 25 homolog C(Cdc25C) [6], [7] and B (Cdc25B) [8].

Progesterone binds both to the plasma membrane-bound and to the intracellular progesterone receptors. Membrane progesterone receptors belong to the G-protein-coupled receptors PAQR family [9], [10], [11]. In human reproductive tissues Progestin and adipoQ receptor family member VII(PAQR7) and Progestin and adipoQ receptor family member VIII(PAQR8) mediate progesterone induction of oocyte maturation. PAQR7 and PAQR8 directly couple to and activate inhibitory G-protein alpha-i to downregulate Adenylate cyclase activity [12], resulting in intracellular cAMP drop [13], [14] and subsequent inhibition of catalytic activity of protein kinase, cAMP-dependent, catalytic (PKA-cat (cAMP-dependent))[15], [16].

Progesterone-depressed PKA-cat (cAMP-dependent) mediates MPF activation by phosphorylation of CDC25C and Cdc25B phosphatases andWee1B kinase [17], [18], [19].

In oocyte, cytoplasm progesterone binds to the classical progesterone receptor - PR (membrane). Ligand-bound receptor associated with Estrogen receptor 1 (ESR1 membrane) [20], [21] activates v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog(c-Src) via direct interaction, resulting in the activation of Son of sevenless homologs (SOS)/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS)/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) cascade [22], [23].

Glycogen synthase kinase-3b (GSK3 beta) is a kinase that phosphorylates and inactivates Aurora kinase A (Aurora-A) [24]. Upon progesterone influence, GSK3 beta is inhibited by phosphorylation on Ser9 [25], known to be a target for the Ribosomal protein S6 kinase, 90kDa protein kinase (p90Rsk) [26], [27].

De novo protein synthesis is essential for meiotic progression to metaphase II. Depressed GSK3 beta leads thereby to the Aurora-A activation, the following phosphorylation of the Cytoplasmic polyadenylation element binding protein 1 (CPEB1) [24], [28], enhanced cytoplasmic mRNA polyadenylation and increased translation of molecules required for oocyte maturation [29], such as v-mos Moloney murine sarcoma viral oncogene homolog (c-Mos) or Speedy homolog A (SPDY1) [29].

In response to progesterone, newly synthesized SPDY1 binds to and activates free monomeric CDK1 (p34), resulting in CDK1 (p34) resistance to inhibitory phosphorylations by Wee1B and Myt1 kinases[30], [31].

In vertebrates progesterone induces MAP kinases activation - the downstream cascade of Mitogen-activated protein kinase kinase 1 (MEK1), Mitogen-activated protein kinase 1(ERK2) and p90Rsk [32]. MAPK cascade is stimulated both through c-Src [22], [23] and by the translational up-regulation of c-Mos [29]. Afterwards ERK2 activates Wee1B [33] and CDC25C [34], and p90Rsk1 inhibits Myt1, thus regulating the CDK1 phosphorylation status and subsequent MPF activation [35].

The Polo-like kinase 1(PLK1) is also a trigger activating MPF in response to progesterone: PLK1 activates Myt1 kinase and inhibits Cdc25C, thereby favoring the formation of CDK1 activity and the initiation of the autoamplification loop [36], as the PLK1 activity is under the control of CDK1 itself [37].

Activated p90Rsk phosphorylates and activates Budding uninhibited by Benzimidazoles 1 homolog (BUB1), leading to the inhibition of Cell division cycle 20 homolog (CDC20), the member of the Anaphase promoting complex (APC), and thus resulting in the metaphase/anaphase transition blockage [32], [38].

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