In mammalian females, oocytes are stored in the ovary and meiosis is arrested at the diplotene stage of prophase I. When females reach puberty oocytes are selectively recruited in cycles to grow, overcome the meiotic arrest, complete the first meiotic division and become mature (ready for fertilization). At a molecular level, the master regulator of prophase I arrest and meiotic resumption is the maturation-promoting factor (MPF) complex, formed by the active form of cyclin dependent kinase 1 (CDK1) and Cyclin B1. However, we still do not have complete information regarding the factors implicated in MPF activation. In this study we document that out of three mammalian serum-glucocorticoid kinase proteins (SGK1, SGK2, SGK3), mouse oocytes express only SGK1 with a phosphorylated (active) form dominantly localized in the nucleoplasm. Further, suppression of SGK1 activity in oocytes results in decreased CDK1 activation via the phosphatase cell division cycle 25B (CDC25B), consequently delaying or inhibiting nuclear envelope breakdown. Expression of exogenous constitutively active CDK1 can rescue the phenotype induced by SGK1 inhibition. These findings bring new insights into the molecular pathways acting upstream of MPF and a better understanding of meiotic resumption control by presenting a new key player SGK1 in mammalian oocytes.

Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic

Laboratory of RNA Biochemistry Department of Genetics and Microbiology Faculty of Science Charles University Viničná 5 Prague 128 44 Czech Republic

School of Animal Sciences AgCenter Louisiana State University Baton Rouge LA 70803 United States

Zobrazit více v PubMed

Adhikari D, Busayavalasa K, Zhang J, Hu M, Risal S, Bayazit MB, Singh M, Diril MK, Kaldis P, Liu K, 2016. Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan. Cell Res. 26, 1212–1225. PubMed PMC

Akaike Y, Chibazakura T, 2020. Aberrant activation of cyclin A-CDK induces G2/M-phase checkpoint in human cells. Cell Cycle 19, 84–96. PubMed PMC

Alamares-Sapuay JG, Martinez-Gil L, Stertz S, Miller MS, Shaw ML, Palese P, 2013. Serum- and glucocorticoid-regulated kinase 1 is required for nuclear export of the ribonucleoprotein of influenza A virus. J. Virol. 87, 6020–6026. PubMed PMC

Berdel HO, Yin H, Liu JY, Grochowska K, Middleton C, Yanasak N, Abdelsayed R, Berdel WE, Mozaffari M, Yu JC, Baban B, 2014. Targeting serum glucocorticoid-regulated Kinase-1 in squamous cell Carcinoma of the head and neck: a novel modality of local control. PLOS ONE 9, e113795. PubMed PMC

Bomberger JM, Coutermarsh BA, Barnaby RL, Sato JD, Chapline MC, Stanton BA, 2014. Serum and Glucocorticoid-inducible Kinase1 increases plasma membrane wt-CFTR in human airway Epithelial cells by inhibiting its Endocytic retrieval. PLOS ONE 9, e89599. PubMed PMC

Bruhn MA, Pearson RB, Hannan RD, Sheppard KE, 2010. Second AKT: The rise of SGK in cancer signalling. Growth Factors 28, 394–408. PubMed

Cazales M, Schmitt E, Montembault E, Dozier C, Prigent C, Ducommun B, 2005. CDC25B Phosphorylation by Aurora A occurs at the G2/M transition and is inhibited by DNA damage. Cell Cycle 4, 1233–1238. PubMed

Chen W, Chen Y, Xu B, Juang Y-C, Stippec S, Zhao Y, Cobb MH, 2009. Regulation of a third conserved Phosphorylation site in SGK1*. J. Biol. Chem. 284, 3453–3460. PubMed PMC

Coleman TR, Dunphy WG, 1994. Cdc2 regulatory factors. Curr. Opin. Cell Biol. 6, 877–882. PubMed

van den Hurk R, Zhao J, 2005. Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. Theriogenology 63, 1717–1751. PubMed

Di Cristofano A, 2017. SGK1: the dark side of PI3K signaling. Curr. Top. Dev. Biol. 123, 49–71. PubMed PMC

Edson MA, Nagaraja AK, Matzuk MM, 2009. The mammalian ovary from genesis to revelation. Endocr. Rev. 30, 624–712. PubMed PMC

Faresse N, Lagnaz D, Debonneville A, Ismailji A, Maillard M, Fejes-Tóth G, Náray-Fejes-Tóth A, Staub O, 2012. Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype. American Journal of Physiology - Renal Physiology 302 (8), F977–85. PubMed

Fejes-Tóth G, Frindt G, Náray-Fejes-Tóth A, Palmer LG, 2008. Epithelial Na+ channel activation and processing in mice lacking SGK1. American Journal of Physiology - Renal Physiology 294 (6), F1298–305. PubMed

Ferencova I, Vaskovicova M, Drutovic D, Knoblochova L, Macurek L, Schultz RM, and Solc P. (under revision). CDC25B is required for the metaphase I-metaphase II transition in mouse oocytes. Journal of Cell Science. PubMed

Gautier J, Minshull J, Lohka M, Glotzer M, Hunt T, Maller JL, 1990. Cyclin is a component of maturation-promoting factor from Xenopus. Cell 60, 487–494. PubMed

Hagting A, Karlsson C, Clute P, Jackman M, Pines J, 1998. MPF localization is controlled by nuclear export. EMBO J. 17, 4127–4138. PubMed PMC

Hiraoka D, Hosoda E, Chiba K, Kishimoto T, 2019. SGK phosphorylates Cdc25 and Myt1 to trigger cyclin B–Cdk1 activation at the meiotic G2/M transition. J. Cell Biol. 218, 3597–3611. PubMed PMC

Hiraoka D, Aono R, Hanada S, Okumura E, Kishimoto T, 2016a. Two new competing pathways establish the threshold for cyclin-B–Cdk1 activation at the meiotic G2/M transition. J. Cell Sci. 129, 3153–3166. PubMed PMC

Hiraoka D, Aono R, Hanada S, Okumura E, Kishimoto T, 2016b. Two new competing pathways establish the threshold for cyclin-B–Cdk1 activation at the meiotic G2/M transition. J. Cell Sci. 129, 3153–3166. PubMed PMC

Homer HA, 2020. The Role of Oocyte quality in explaining “unexplained” infertility. Semin Reprod. Med. 38, 21–28. PubMed

Hosoda E, Hiraoka D, Hirohashi N, Omi S, Kishimoto T, Chiba K, 2019. SGK regulates pH increase and cyclin B–Cdk1 activation to resume meiosis in starfish ovarian oocytes. J. Cell Biol. 218, 3612–3629. PubMed PMC

Kalous J, Solc P, Baran V, Kubelka M, Schultz RM, Motlik J, 2006. PKB/AKT is involved in resumption of meiosis in mouse oocytes. Biol. Cell 98, 111–123. PubMed

Keefe D, Kumar M, Kalmbach K, 2015. Oocyte competency is the key to embryo potential. Fertil. Steril. 103, 317–322. PubMed

Kobayashi T, Cohen P, 1999. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem. J. 339 (Pt 2), 319–328. PubMed PMC

Kobayashi T, Deak M, Morrice N, Cohen P, 1999. Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem J. 344 (Pt 1), 189–197. PubMed PMC

Koncicka M, Tetkova A, Jansova D, Del Llano E, Gahurova L, Kracmarova J, Prokesova S, Masek T, Pospisek M, Bruce AW, Kubelka M, Susor A, 2018. Increased expression of maturation promoting factor components speeds up Meiosis in Oocytes from aged females. Int. J. Mol. Sci. 19, 2841. PubMed PMC

Krisher RL, 2004. The effect of oocyte quality on development. J. Anim. Sci. 82, E14–E23. PubMed

Lang F, Cohen P, 2001. Regulation and physiological roles of serum- and Glucocorticoid-induced protein Kinase isoforms. Sci. STKE 2001, re17. PubMed

Lien EC, Dibble CC, Toker A, 2017. PI3K signaling in cancer: beyond AKT. Curr. Opin. Cell Biol. 45, 62–71. PubMed PMC

Lincoln AJ, Wickramasinghe D, Stein P, Schultz RM, Palko ME, De Miguel MPD, Tessarollo L, Donovan PJ, 2002. Cdc25b phosphatase is required for resumption of meiosis during oocyte maturation. Nat. Genet 30, 446–449. PubMed

del Llano E, Masek T, Gahurova L, Pospisek M, Koncicka M, Jindrova A, Jansova D, Iyyappan R, Roucova K, Bruce AW, Kubelka M, Susor A, 2020. Age-related differences in the translational landscape of mammalian oocytes. Aging Cell 19, e13231. PubMed PMC

Masek T, Del Llano E, Gahurova L, Kubelka M, Susor A, Roucova K, Lin C-J, Bruce AW, Pospisek M, 2020. Identifying the translatome of mouse NEBD-stage oocytes via SSP-profiling; a novel Polysome fractionation method. Int J. Mol. Sci. 21, E1254. PubMed PMC

Murray JT, Campbell DG, Morrice N, Auld GC, Shpiro N, Marquez R, Peggie M, Bain J, Bloomberg GB, Grahammer F, Lang F, Wulff P, Kuhl D, Cohen P, 2004. Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3. Biochem. J. 384, 477–488. PubMed PMC

Norris RP, Ratzan WJ, Freudzon M, Mehlmann LM, Krall J, Movsesian MA, Wang H, Ke H, Nikolaev VO, Jaffe LA, 2009. Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte. Development 136, 1869–1878. PubMed PMC

Pan B, Li J, 2019. The art of oocyte meiotic arrest regulation. Reprod. Biol. Endocrinol. 17, 8. PubMed PMC

Pirino G, Wescott MP, Donovan PJ, 2009. Protein Kinase A regulates resumption of meiosis by phosphorylation of Cdc25B in mammalian oocytes. Cell Cycle 8, 665–670. PubMed

Potireddy S, Vassena R, Patel BG, Latham KE, 2006. Analysis of polysomal mRNA populations of mouse oocytes and zygotes: Dynamic changes in maternal mRNA utilization and function. Dev. Biol. 298, 155–166. PubMed

Roberts EC, Shapiro PS, Nahreini TS, Pages G, Pouyssegur J, Ahn NG, 2002. Distinct cell cycle timing requirements for extracellular signal-regulated Kinase and Phosphoinositide 3-Kinase signaling pathways in somatic cell Mitosis. Mol. Cell Biol. 22, 7226–7241. PubMed PMC

Schmidt M, Rohe A, Platzer C, Najjar A, Erdmann F, Sippl W, 2017. Regulation of G2/M transition by inhibition of WEE1 and PKMYT1 Kinases. Molecules 22, 2045. PubMed PMC

Sharma A, Tiwari M, Gupta A, Pandey AN, Yadav PK, Chaube SK, 2018. Journey of oocyte from metaphase-I to metaphase-II stage in mammals. J. Cell. Physiol. 233, 5530–5536. PubMed

Sherk AB, Frigo DE, Schnackenberg CG, Bray JD, Laping NJ, Trizna W, Hammond M, Patterson JR, Thompson SK, Kazmin D, Norris JD, McDonnell DP, 2008. Development of a small-molecule serum- and glucocorticoid-regulated Kinase-1 antagonist and its evaluation as a prostate cancer therapeutic. Cancer Res. 68, 7475–7483. PubMed PMC

Solc P, Saskova A, Baran V, Kubelka M, Schultz RM, Motlik J, 2008. CDC25A phosphatase controls meiosis I progression in mouse oocytes. Dev. Biol. 317, 260–269. PubMed PMC

Tetkova A, Hancova M, 2016. Mouse oocyte isolation. Cultiv. RNA Micro Bio-Protoc. 6, e1729.

Tripathi A, Kumar KVP, Chaube SK, 2010. Meiotic cell cycle arrest in mammalian oocytes. J. Cell. Physiol. 223, 592–600. PubMed

Xiao L, Han X, Wang X, Li Q, Shen P, Liu Z, Cui Y, Chen Y, 2019. Spinal serum- and glucocorticoid-regulated Kinase 1 (SGK1) signaling contributes to Morphine-induced Analgesic tolerance in rats. Neuroscience 413, 206–218. PubMed

Zeng F, Baldwin DA, Schultz RM, 2004. Transcript profiling during preimplantation mouse development. Dev. Biol. 272, 483–496. PubMed

CHK1-CDC25A-CDK1 regulate cell cycle progression and protect genome integrity in early mouse embryos