BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Adequate concentration of B cell leukemia/lymphoma 3 (Bcl3) is required for pluripotency and self-renewal of mouse embryonic stem cells via downregulation of Nanog transcription

  • Kang, Songhwa (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Yun, Jisoo (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Kim, Da Yeon (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Jung, Seok Yun (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Kim, Yeon Ju (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Park, Ji Hye (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Ji, Seung Taek (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Jang, Woong Bi (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Ha, Jongseong (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University) ;
  • Kim, Jae Ho (Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital) ;
  • Baek, Sang Hong (Laboratory of Cardiovascular Disease, Division of Cardiology, School of Medicine, The Catholic University) ;
  • Kwon, Sang-Mo (Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University)
  • Received : 2017.11.20
  • Accepted : 2018.01.09
  • Published : 2018.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

B cell leukemia/lymphoma 3 (Bcl3) plays a pivotal role in immune homeostasis, cellular proliferation, and cell survival, as a co-activator or co-repressor of transcription of the $NF-{\kappa}B$ family. Recently, it was reported that Bcl3 positively regulates pluripotency genes, including Oct4, in mouse embryonic stem cells (mESCs). However, the role of Bcl3 in the maintenance of pluripotency and self-renewal activity is not fully established. Here, we report the dynamic regulation of the proliferation, pluripotency, and self-renewal of mESCs by Bcl3 via an influence on Nanog transcriptional activity. Bcl3 expression is predominantly observed in immature mESCs, but significantly decreased during cell differentiation by LIF depletion and in mESC-derived EBs. Importantly, the knockdown of Bcl3 resulted in the loss of self-renewal ability and decreased cell proliferation. Similarly, the ectopic expression of Bcl3 also resulted in a significant reduction of proliferation, and the self-renewal of mESCs was demonstrated by alkaline phosphatase staining and clonogenic single cell-derived colony assay. We further examined that Bcl3-mediated regulation of Nanog transcriptional activity in mESCs, which indicated that Bcl3 acts as a transcriptional repressor of Nanog expression in mESCs. In conclusion, we demonstrated that a sufficient concentration of Bcl3 in mESCs plays a critical role in the maintenance of pluripotency and the self-renewal of mESCs via the regulation of Nanog transcriptional activity.

Keywords

References

  1. Suda Y, Suzuki M, Ikawa Y and Aizawa S (1987) Mouse embryonic stem cells exhibit indefinite proliferative potential. J Cell Physiol 133, 197-201 https://doi.org/10.1002/jcp.1041330127
  2. Niwa H (2007) How is pluripotency determined and maintained? Development 134, 635-646 https://doi.org/10.1242/dev.02787
  3. Chambers I, Colby D, Robertson M et al (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643-655 https://doi.org/10.1016/S0092-8674(03)00392-1
  4. Mitsui K, Tokuzawa Y, Itoh H et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631-642 https://doi.org/10.1016/S0092-8674(03)00393-3
  5. Boyer LA, Lee TI, Cole MF et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947-956 https://doi.org/10.1016/j.cell.2005.08.020
  6. Chambers I, Silva J, Colby D et al (2007) Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230-1234 https://doi.org/10.1038/nature06403
  7. Kuroda T, Tada M, Kubota H et al (2005) Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Mol Cell Biol 25, 2475-2485 https://doi.org/10.1128/MCB.25.6.2475-2485.2005
  8. Rodda DJ, Chew JL, Lim LH et al (2005) Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 280, 24731-24737 https://doi.org/10.1074/jbc.M502573200
  9. van den Berg DL, Zhang W, Yates A et al (2008) Estrogen-related receptor beta interacts with Oct4 to positively regulate Nanog gene expression. Mol Cell Biol 28, 5986-5995 https://doi.org/10.1128/MCB.00301-08
  10. Ohno H, Takimoto G and McKeithan TW (1990) The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell 60, 991-997 https://doi.org/10.1016/0092-8674(90)90347-H
  11. Maldonado V and Melendez-Zajgla J (2011) Role of Bcl-3 in solid tumors. Mol Cancer 10, 152 https://doi.org/10.1186/1476-4598-10-152
  12. Fujita T, Nolan GP, Liou HC, Scott ML and Baltimore D (1993) The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-kappa B p50 homodimers. Genes Dev 7, 1354-1363 https://doi.org/10.1101/gad.7.7b.1354
  13. Inoue J, Takahara T, Akizawa T and Hino O (1993) Bcl-3, a member of the I kappa B proteins, has distinct specificity towards the Rel family of proteins. Oncogene 8, 2067-2073
  14. Na S-Y, Choi J-E, Kim H-J, Jhun BH, Lee Y-C and Lee JW (1999) Bcl3, an $l{\kappa}B$ protein, stimulates activating protein-1 transactivation and cellular proliferation. J Biol Chem 274, 28491-28496 https://doi.org/10.1074/jbc.274.40.28491
  15. Na S-Y, Choi H-S, Kim JW, Na DS and Lee JW (1998) Bcl3, an $l{\kappa}B$ protein, as a novel transcription coactivator of the retinoid X receptor. J Biol Chem 273, 30933-30938 https://doi.org/10.1074/jbc.273.47.30933
  16. Hishiki T, Ohshima T, Ego T and Shimotohno K (2007) BCL3 acts as a negative regulator of transcription from the human T-cell leukemia virus type 1 long terminal repeat through interactions with TORC3. J Biol Chem 282, 28335-28343 https://doi.org/10.1074/jbc.M702656200
  17. Chen CY, Lee DS, Yan YT et al (2015) Bcl3 Bridges LIF-STAT3 to Oct4 Signaling in the Maintenance of Naive Pluripotency. Stem Cells 33, 3468-3480 https://doi.org/10.1002/stem.2201
  18. Bours V, Franzoso G, Azarenko V et al (1993) The oncoprotein Bcl-3 directly transactivates through ${\kappa}B$ motifs via association with DNA-binding p50B homodimers. Cell 72, 729-739 https://doi.org/10.1016/0092-8674(93)90401-B
  19. Park SG, Chung C, Kang H, Kim J-Y and Jung G (2006) Up-regulation of cyclin D1 by HBx is mediated by NF-${\kappa}B2$/BCL3 complex through ${\kappa}B$ site of cyclin D1 promoter. J Biol Chem 281, 31770-31777 https://doi.org/10.1074/jbc.M603194200
  20. Loh YH, Wu Q, Chew JL et al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38, 431-440 https://doi.org/10.1038/ng1760
  21. Jamaluddin M, Choudhary S, Wang S et al (2005) Respiratory syncytial virus-inducible BCL-3 expression antagonizes the STAT/IRF and NF-${\kappa}B$ signaling pathways by inducing histone deacetylase 1 recruitment to the interleukin-8 promoter. J Virol 79, 15302-15313 https://doi.org/10.1128/JVI.79.24.15302-15313.2005
  22. Yang J, Williams RS and Kelly DP (2009) Bcl3 interacts cooperatively with peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) coactivator $1{\alpha}$ to coactivate nuclear receptors estrogen-related receptor ${\alpha}$ and $PPAR{\alpha}$. Mol Cell Biol 29, 4091-4102 https://doi.org/10.1128/MCB.01669-08
  23. Viatour P, Dejardin E, Warnier M et al (2004) GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol Cell 16, 35-45 https://doi.org/10.1016/j.molcel.2004.09.004
  24. Lin T, Chao C, Saito S et al (2005) p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 7, 165-171 https://doi.org/10.1038/ncb1211