Hostname: page-component-76fb5796d-qxdb6 Total loading time: 0 Render date: 2024-04-26T04:17:58.343Z Has data issue: false hasContentIssue false
  • English
  • Français

Akt/PKB plays role of apoptosis relay on entry into first mitosis of mouse embryo

Published online by Cambridge University Press:  09 May 2013

Vladimir Baran ,
Dusan Fabian  and
Pavol Rehak
Vladimir Baran*
Affiliation:
Institute of Animal Physiology, Slovak Academy of Sciences, Soltesovej 4, 040 01 Kosice, Slovakia.
Dusan Fabian
Affiliation:
Institute of Animal Physiology, Slovak Academy of Sciences, Soltesovej 4, 040 01 Kosice, Slovakia.
Pavol Rehak
Affiliation:
Institute of Animal Physiology, Slovak Academy of Sciences, Soltesovej 4, 040 01 Kosice, Slovakia.
*
All correspondence to: Vladimir Baran, Institute of Animal Physiology, Slovak Academy of Sciences, Soltesovej 4, 040 01 Kosice, Slovakia. e-mail: baran@saske.sk
Get access Rights & Permissions [Opens in a new window]

Summary

The cell-cycle regulators that control meiotic divisions also regulate the events that accompany the oocyte-to-zygote transition. Thus, the meiotic machinery functions as an internal pacemaker that propels the oocyte toward embryogenesis. The preimplantation embryo expresses a number of receptors that are important for initial activity of the phosphatidylinositol 3-kinase–protein kinase B (PI3K-Akt/PKB) pathway. The complete PI3K-Akt/PKB-CDK1 cascade is implicated as a key regulator of a number of cellular functions. Selective inhibition of protein kinase B (Akt/PKB) with inhibitor SH6 and cyclin-dependent kinase 1 (CDK1) with inhibitor roscovitine arrest development of the 1-cell preimplantation mouse embryo before entry into the first mitosis. The pronuclei of these inhibited embryos migrate to one another, but do not progress to pronuclei envelope breakdown and pronuclear fusion running immediately before the onset of mitosis. SH6-treated 1-cell mouse embryos showed a high occurrence of apoptosis features (nuclear fragmentation, positive terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), active caspase-3 in both cytoplasm and nucleoplasm). In the Akt/PKB-inhibited embryos, the active phosphorylated form Ser473Akt/PKB was not detected in pronuclear areas when compared with inhibitor-free controls. Although CDK1-inhibited 1-cell embryos also failed to enter into the first mitosis, the presence of apoptotic cell death features was not observed. In the roscovitine-treated embryos, Ser473Akt/PKB was detected in the pronuclei independently of CDK1 activity. We conclude that Akt/PKB plays an important role during entry of the 1-cell mouse embryo into the first mitosis, and probably functions as a relay in the cell-cycle stage. We assume that Akt/PKB is the primary target responsible for mediating anti-apoptotic signals in the 1-cell mouse embryo.

Keywords

ApoptosisAkt kinaseMouse zygoteRoscovitineSH6
Type
Research Article
Information
Zygote , Volume 21 , Issue 4 , November 2013 , pp. 406 - 416
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bellacosa, A., Sakaue, H., Nedachi, T., Kovacina, K.S., Clayberger, C., Conti, M. & Roth, R.A. (1991). A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254, 274–7.Google ScholarPubMed
Brunet, A., Park, J., Tran, H., Hu, L.S., Hemmings, B.A. & Greenberg, M.E. (2001). Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL (FOXO3a). Mol. Cell. Biol. 21, 952–65.CrossRefGoogle Scholar
Chao, X., Zao, J., Xiao-Yi, G., Li-Jun, M. & Tao, S. (2010). Blocking of PI3K/AKT induces apoptosis by its effect on NF-κB activity in gastric carcinoma cell line SGC7901. Biomed. Pharmacol. 64, 600–4.CrossRefGoogle ScholarPubMed
Chrysis, D., Zaman, F., Chagin, A.S., Takigawa, M. & Savendahl, L. (2005). Dexamethasone induces apoptosis in proliferative chondrocytes through activation of caspase and suppression of the Akt-phosphatidylinositol 3′-kinase signaling pathway. Endocrinology 146, 1391–7.CrossRefGoogle Scholar
Clark, A.S., West, K., Streicher, S. & Dennis, P.A. (2002). Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. 1, 707–17.Google ScholarPubMed
Corry, G.N., Tanasijevic, B., Barry, E.R., Krueger, W. & Rasmussen, T.P. (2009). Epigenetic regulatory mechanisms during preimplantation development. Birth Defects Res C Embryo Today 87, 297–313.CrossRefGoogle ScholarPubMed
Darzynkiewicz, Z., Bedner, E. & Traganos, F. (2001). Difficulties and pitfalls in analysis of apoptosis. Methods Cell Biol. 63, 527–46.CrossRefGoogle ScholarPubMed
Downward, J. (2004). PI 3-kinase, Akt and cell survival. Semin. Cell Dev. Biol. 15, 177–182.CrossRefGoogle ScholarPubMed
Fabian, D., Koppel, J. & Maddox-Hyttel, P. (2005). Apoptotic processes during mammalian preimplantation development. Theriogenology 64, 221–31.CrossRefGoogle ScholarPubMed
Fabian, D., Juhás, S., Ilkova, G. & Koppel, J. (2007). Dose- and time-dependent effects of TNFalpha and actinomycin D on cell death incidence and embryo growth in mouse blastocysts. Zygote 15, 241–9.CrossRefGoogle ScholarPubMed
Fabian, D., Bukovska, A., Juhas, S. & Koppel, J. (2009). Apoptotic processes and DNA cytosine methylation in mouse embryos arrested at the 2-cell stage. Zygote 17, 269–79.CrossRefGoogle Scholar
Feng, C., Yu, A., Liu, Y., Zhang, J., Zong, Z., Su, W., Zhang, Z., Yu, D., Sun, Q.Y. & Yu, B. (2007). Involvement of protein kinase B/AKT in early development of mouse fertilized eggs. Biol. Reprod. 77, 560–8.CrossRefGoogle ScholarPubMed
Gavet, O. & Pines, J. (2010). Activation of cyclinB1-Cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis. J. Cell Biol. 189, 247–59.CrossRefGoogle Scholar
Hemstrom, T.H., Sandstrom, M. & Zhivotovsky, B. (2006). Inhibitors of the PI3-kinase/Akt pathway induce mitotic catastrophe in non-small cell lung cancer cells. Int. J. Cancer 119, 1028–38.CrossRefGoogle ScholarPubMed
Hosino, Y., Yokoo, M., Yoshida, N., Sasada, H., Matsumoto, H. & Satao, E. (2004). Phosphatidylinositol 3-kinase and Akt participate in the FSH-induced meiotic maturation of mouse oocytes. Mol. Reprod. Dev. 69, 77–86.CrossRefGoogle Scholar
Kim, A.H., Khursigara, G., Sun, X., Franke, T.F. & Chao, M.V. (2001). Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol. Cell. Biol. 21, 893–901.CrossRefGoogle ScholarPubMed
Kalous, J., Solc, P., Baran, V., Kubelka, M., Schultz, R.M. & Motlik, J. (2006). PKB/Akt is involved in resumption of meiosis in mouse oocytes. J. Biol. Cell 98, 111–23.Google ScholarPubMed
Kops, G.J. & Burgering, B.M. (1999). Forkhead transcription factors: new insight into protein kinase B (c-Akt) signaling. J. Mol. Med. 77, 656–65.CrossRefGoogle ScholarPubMed
Kops, G.J., deRuiter, N.D., deVries-Smith, A.M., Powell, D.R., Bos, J.L. & Burgering, B.M. (1999b) Direct control of the forkhead transcription factor AFX by protein kinase B. Nature 398, 630–4.CrossRefGoogle ScholarPubMed
Kozikowski, A.P., Sun, H., Brognard, J. & Dennis, P.A. (2003). Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt. J. Am. Chem. Soc. 125, 1144–5.CrossRefGoogle ScholarPubMed
Li, Y., Chandrakanthan, V., Day, L.M. & O'Neill, C. (2007). Direct evidence for the action of phosphatidylinositol (3,4,5)-triphosphate-mediated signal transduction in the 2-cell mouse embryo. Biol. Reprod. 77, 813–21.CrossRefGoogle Scholar
Lighten, A.D., Hardy, K., Winston, R.M.L. & Moore, G.E. (1997). Expression of mRNA for the insulin-like growth factors and their receptors in human preimplantation embryos. Mol. Reprod. Dev. 47, 134–9.3.0.CO;2-N>CrossRefGoogle ScholarPubMed
Lonergan, P., Faerge, I., Maddox-Hyttel, P., Boland, M. & Fair, T. (2003). Ultrastructural modification in bovine oocytes maintained in meiotic arrest in vitro using roscovitine or butyrolactone. Mol. Reprod. Dev. 64, 369–78.CrossRefGoogle ScholarPubMed
Marchal, R., Tomanek, M., Terqui, M. & Mermillod, P. (2001). Effects of cell cycle dependent kinase inhibitor on nuclear and cytoplasmic maturation of porcine oocytes. Mol. Reprod. Dev. 60, 65–73.CrossRefGoogle ScholarPubMed
Martinez, F., Rienzi, L., Iacobelli, M., Ubaldi, F., Mendoza, C., Greco, E. & Tesarik, J. (2002). Caspase activity in preimplantation human embryos is not associated with apoptosis. Hum. Reprod. 17, 1584–90.CrossRefGoogle Scholar
Meijer, L., Borgne, A., Mulner, O., Chong, J.P., Blow, J.J., Delcros, J.G. & Moulinoux, J.P. (1997). Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinase cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 521–36.CrossRefGoogle ScholarPubMed
Mermillod, P., Tomanek, M., Marchal, R. & Maier, L. (2000). High developmental competence of cattle oocytes maintained at the germinal vesicle stage for 24 hours in culture by specific inhibition of MPF kinase activity. Mol. Reprod. Dev. 55, 89–95.3.0.CO;2-M>CrossRefGoogle ScholarPubMed
Mikami, I., Zhang, F., Hirata, T., Okamoto, J., Koizumi, K., Shimizu, K., Jablons, D. & He, B. (2010). Inhibition of activated phosphatidylinositol 3-kinase/AKT pathway in malignant pleural mesothelioma leads to G1 cell cycle arrest. Oncol. Rep. 24, 1677–81.Google ScholarPubMed
Nurse, P. (1990). Universal control mechanism regulating onset of M-phase. Nature 344, 503–8.CrossRefGoogle ScholarPubMed
Okumura, E., Fukuhara, T., Yoshida, H., Hanada, S., Koyutsumi, R., Mori, M., Tachibana, K. & Kishimoto, T. (2002). Akt inhibits Myt1 in the signalling pathway that leads to meiotic G2/M-phase transition Nature Cell Biol. 4, 111–6.CrossRefGoogle ScholarPubMed
O'Neill, C. (2008a). Phosphatidylinositol 3-kinase signaling in mammalian preimplantation embryo development. Reproduction 136, 147–56.CrossRefGoogle ScholarPubMed
O'Neill, C. (2008b). The potential roles for embryotrophic ligands in preimplantation embryo development. Hum. Reprod. Update 14, 275–88.CrossRefGoogle ScholarPubMed
Osaki, M., Oshimura, M. & Ito, H. (2004). PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis 9, 667–76.CrossRefGoogle ScholarPubMed
Papandile, A., Tyas, D., O'Malley, D.M. & Warner, C.M. (2004). Analysis of caspase-3, caspase-8 and caspase-9 enzymatic activities in mouse oocytes and zygotes. Zygote 12, 57–64.CrossRefGoogle ScholarPubMed
Perez, G.I., Tao, X.J. & Tilly, J.L. (1999). Fragmentation and death (a.k.a. apoptosis) of ovulated oocytes. Mol. Hum. Reprod. 5, 414–20.CrossRefGoogle ScholarPubMed
Riley, J.K., Carayannopoulos, M.O., Wyman, A.H., Chi, M., Ratajczak, C.K. & Moley, K.H. (2005). The Akt/PKB pathway is present and functional in the preimplantation mouse embryo. Dev. Biol. 284, 377–86.CrossRefGoogle Scholar
Riley, J.K., Carayannopoulos, M.O., Wyman, A.H., Chi, M. & Moley, K.H. (2006). Phosphatidylinositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts. J. Biol. Chem. 281, 6010–9.CrossRefGoogle ScholarPubMed
Rojo, M.C. & Gonzalez, M.E. (1998). In situ detection of apoptotic cells by TUNEL in the gill epithelium of the developing brown trout (Salmo trutta). J. Anat. 193, 391–8.CrossRefGoogle Scholar
Saskova, A., Solc, P., Baran, V., Kubelka, M., Schultz, R.M. & Motlik, J. (2008). Aurora kinase A controls meiosis I progression in mouse oocytes. Cell Cycle 7, 2368–76.CrossRefGoogle ScholarPubMed
Schied, W.P. & Woodget, P.A. (2003). Unraveling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 546, 1089–112.Google Scholar
Shi, Y., Liu, X., Han, E.K., Guan, R., Shoemaker, A.R., Oleksijew, A., Woods, K.W., Fisher, J.P., Klinghofer, V., Lasko, L., McGonidal, T., Li, Q., Rosenberg, S.H., Giranda, V.L. & Luo, Y. (2005). Neoplasia 7, 992–1000.CrossRefGoogle Scholar
Stitzel, M.L. & Seydoux, G. (2007). Regulation of the oocyte-to-zygote transition. Science 316, 407–408.CrossRefGoogle ScholarPubMed
Tachibana, K., Hara, M., Hattori, Y. & Kishimoto, T. (2008). Cyclin B-Cdk1 controls pronuclear union in interphase. Curr. Biol. 18, 1308–13.CrossRefGoogle ScholarPubMed
Tomek, W. & Smiljakovic, T. (2005). Activation of Akt (protein kinase B) stimulates metaphase I to metaphase II transition in bovine oocytes. Reproduction 130, 423–30.CrossRefGoogle ScholarPubMed
Vlahos, C.J., Matter, W.F., Hui, K.Y. & Brown, R.F. (1994). A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 269, 5241–8.CrossRefGoogle ScholarPubMed
Wheeldon, E.B., Williams, S.M., Soames, A.R., James, N.H. & Roberts, R.A. (1995). Quantitation of apoptotic bodies in rat liver by in situ end labelling (ISEL): correlation with morphology. Toxicol. Pathol. 23, 410–15.CrossRefGoogle ScholarPubMed
Wijsman, J.H., Jonker, R.R., Keijzer, R., van de Velde, C.J., Cornelisse, C.J. & van Dierendonck, J.H. (1993). A new method to detect apoptosis in paraffin sections: in situ end-labelling of fragmented DNA. J. Histochem. Cytochem. 41, 7–12.CrossRefGoogle Scholar
Zachariae, W. & Nasmyth, K. (1999). Whose and is destruction: cell division and the anaphase-promoting complex. Genes Dev. 13, 2039–58.CrossRefGoogle ScholarPubMed