Share This Article:

Intracellular Notch1 May Induce a Conformational Change in CSL/DNA, without Forming ICN1/CSL/DNA Molecular Complex, in Vitro

Abstract Full-Text HTML Download Download as PDF (Size:2350KB) PP. 73-95
DOI: 10.4236/cellbio.2013.22010    2,677 Downloads   5,076 Views   Citations

ABSTRACT

Intracellular Notch (ICN) initiates DNA transcription in cooperation with CSL that acts as repressor in the absence of ICN. The ICN mediates recruitment of MAML protein, leading to the formation of minimal transcriptional complex, MAML/ICN/CSL/DNA. Crystal structure reveals that different conformations exist between the free (CSL/DNA) and bound (ICN/MAML/CSL/DNA) forms. The significance of this modulation of the CSL/DNA molecular complex can be better understood by experimental approaches that aim to elucidate the cause and timing of these events. There are four orthologues of human ICN (ICN1-4). We studied interactions between human full-length ICN1 and CSL/DNA without involvement of MAML, in vitro, and found that 1) the EMSA profile of CSL/DNA is altered in the presence of ICN1 as a consequence of an intrinsic change(s) in CSL/DNA, and not due to the formation of an ICN/CSL/DNA molecular complex; 2) ICN1 destabilizes CSL/DNA. These findings indicate that human ICN1 functions to modulate the CSL/DNA molecular complex for subsequent recruitment of MAML, and that modulated CSL/DNA cannot accommodate ICN1 in the absence of MAML. The latter in turn, implies that the formation of the MAML/ICN1/CSL/DNA is likely to be a collective event, wherein preassembly of MAML and ICN1 as a binary complex co-localizes at the CSL/DNA promoter site, or the MAML/ICN1/CSL complex is pre-assembled prior to binding to the promoter, rather than ICN1 arriving at CSL/DNA ahead of MAML and/or other associated transcription factors. The novel finding that ICN1 destabilizes the CSL/DNA complex opens new possibilities of transcriptional regulation by Notch.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

A. Stortchevoi, "Intracellular Notch1 May Induce a Conformational Change in CSL/DNA, without Forming ICN1/CSL/DNA Molecular Complex, in Vitro," CellBio, Vol. 2 No. 2, 2013, pp. 73-95. doi: 10.4236/cellbio.2013.22010.

References

[1] G. Weinmaster and C. Kintner, “Modulation of Notch Signaling during Somitogenesis,” Annual Review of Cell and Developmental Biology, Vol. 19, 2003, pp. 367-395. doi:10.1146/annurev.cellbio.19.111301.115434
[2] J. S. Mumm and R. Kopan, “Notch Signaling: From the Outside in,” Developmental Biology, Vol. 228, No. 2, 2000, pp. 151-165. doi:10.1006/dbio.2000.9960
[3] M. V. Gustafsson, et al., “Hypoxia Requires Notch Signaling to Maintain the Undifferentiated Cell State,” Developmental Cell, Vol. 9, No. 5, 2005, pp. 617-628. doi:10.1016/j.devcel.2005.09.010
[4] G. D. Hurlbut, et al., “Crossing paths with Notch in the Hyper-Network,” Current Opinion in Cell Biology, Vol. 19, No. 2, 2007, pp. 166-175. doi:10.1016/j.ceb.2007.02.012
[5] F. Jundt, R. Schwarzer and B. Dorken, “Notch Signaling in Leukemias and Lymphomas,” Current Molecular Medicine, Vol. 8, No. 1, 2008, pp. 51-59. doi:10.2174/156652408783565540
[6] R. M. Demarest, F. Ratti and A. J. Capobianco, “It’s TALL about Notch,” Oncogene, Vol. 27, No. 38, 2008, pp. 5082-5091. doi:10.1038/onc.2008.222
[7] F. Wu, A. Stutzman and Y. Y. Mo, “Notch Signaling and Its Role in Breast Cancer,” Frontiers in Bioscience, Vol. 12, 2007, pp. 4370-4383. doi:10.2741/2394
[8] M. Roy, W. S. Pear and J. C. Aster, “The Multifaceted Role of Notch in Cancer,” Current Opinion in Genetics & Development, Vol. 17, No. 1, 2007, pp. 52-59. doi:10.1016/j.gde.2006.12.001
[9] U. Koch and F. Radtke, “Notch and Cancer: A Double-Edged Sword,” Cellular and Molecular Life Sciences, Vol. 64, No. 21, 2007. pp. 2746-2762. doi:10.1007/s00018-007-7164-1
[10] Z. Wang, et al., “Exploitation of the Notch Signaling Pathway as a Novel Target for Cancer Therapy,” Anticancer Research, Vol. 28, No. 6A, 2008, pp. 3621-3630.
[11] M. A. Villaronga, C. L. Bevan and B. Belandia, “Notch Signaling: A Potential Therapeutic Target in Prostate Cancer,” Current Cancer Drug Targets, Vol. 8, No. 7, 2008, pp. 566-580. doi:10.2174/156800908786241096
[12] P. Rizzo, et al., “Rational Targeting of Notch Signaling in Cancer,” Oncogene, Vol. 27, No. 38, 2008, pp. 5124-5131. doi:10.1038/onc.2008.226
[13] R. Kopan and M. X. Ilagan, “The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism,” Cell, Vol. 137, No. 2, 2009, pp. 216-233. doi:10.1016/j.cell.2009.03.045
[14] M. E. Fortini, “Notch Signaling: The Core Pathway and Its Posttranslational Regulation,” Developmental Cell, Vol. 16, No. 5, 2009, pp. 633-647. doi:10.1016/j.devcel.2009.03.010
[15] T. Borggrefe and F. Oswald, “The Notch Signaling Pathway: Transcriptional Regulation at Notch Target Genes,” Cellular and Molecular Life Sciences, Vol. 66, No. 10, 2009, pp. 1631-1646. doi:10.1007/s00018-009-8668-7
[16] M. Le Gall and E. Giniger, “Identification of Two Binding Regions for the Suppressor of Hairless Protein within the Intracellular Domain of Drosophila Notch,” The Journal of Biological Chemistry, Vol. 279, No. 28, 2004, pp. 29418-29426. doi:10.1074/jbc.M404589200
[17] H. Y. Kao, et al., “A Histone Deacetylase Corepressor Complex Regulates the Notch Signal Transduction Pathway,” Genes & Development, Vol. 12, No. 15, 1998, pp. 2269-2277. doi:10.1101/gad.12.15.2269
[18] J. J. Hsieh, et al., “CIR, a Corepressor Linking the DNA Binding Factor CBF1 to the Histone Deacetylase Complex,” Proceedings of the National Academy of Sciences of USA, Vol. 96, No. 1, 1999, pp. 23-28. doi:10.1073/pnas.96.1.23
[19] F. Oswald, et al., “RBP-Jkappa/SHARP Recruits CtIP/ CtBP Corepressors to Silence Notch Target Genes,” Molecular and Cellular Biology, Vol. 25, No. 23, 2005, pp. 10379-10390. doi:10.1128/MCB.25.23.10379-10390.2005
[20] C. J. Fryer, et al., “Mastermind Mediates Chromatin-Specific Transcription and Turnover of the Notch Enhancer Complex,” Genes & Development, Vol. 16, No. 11, 2002, pp. 1397-1411. doi:10.1101/gad.991602
[21] A. G. Petcherski and J. Kimble, “Mastermind Is a Putative Activator for Notch,” Current Biology, Vol. 10, No. 13, 2000, pp. R471-473. doi:10.1016/S0960-9822(00)00577-7
[22] L. Wu, et al., “MAML1, a Human Homologue of Drosophila Mastermind, Is a Transcriptional Co-Activator for NOTCH Receptors,” Nature Genet, Vol. 26, No. 4, 2000, pp. 484-489. doi:10.1038/82644
[23] S. Zhou, et al., “A Role for SKIP in EBNA2 Activation of CBF1-Repressed Promoters,” Journal of Virology, Vol. 74, No. 4, 2000, pp. 1939-1947. doi:10.1128/JVI.74.4.1939-1947.2000
[24] L. Espinosa, et al., “Phosphorylation by Glycogen Synthase Kinase-3 Beta Down-Regulates Notch Activity, a Link for Notch and Wnt Pathways,” Journal of Biological Chemistry, Vol. 278, No. 34, 2003, pp. 32227-32235. doi:10.1074/jbc.M304001200
[25] H. Qin, et al., “RING1 Inhibits Transactivation of RBP-J by Notch through Interaction with LIM Protein KyoT2,” Nucleic Acids Research, Vol. 32, No. 4, 2004, pp. 1492-1501. doi:10.1093/nar/gkh295
[26] F. Oswald, et al., “p300 Acts as a Transcriptional Coactivator for Mammalian Notch-1,” Molecular and Cellular Biology, Vol. 21, No. 22, 2001, pp. 7761-7774. doi:10.1128/MCB.21.22.7761-7774.2001
[27] E. A. Johnson, “HIF Takes It Up a Notch,” Science Signal, Vol. 4, No. 181, 2011, p. pe33. doi:10.1126/scisignal.2002277
[28] C. J. Fryer, J. B. White and K. A. Jones, Mastermind Recruits CycC:CDK8 to Phosphorylate the Notch ICD and Coordinate Activation with Turnover,” Molecular Cell, Vol. 16, No. 4, 2004, pp. 509-520. doi:10.1016/j.molcel.2004.10.014
[29] Y. Nam, et al., “Structural Basis for Cooperativity in Recruitment of MAML Coactivators to Notch Transcription Complexes,” Cell, Vol. 124, No. 5, 2006, pp. 973-983. doi:10.1016/j.cell.2005.12.037
[30] R. A. Kovall and W. A. Hendrickson, “Crystal Structure of the Nuclear Effector of Notch Signaling, CSL, Bound to DNA,” The EMBO Journal, Vol. 23, No. 17, 2004, pp. 3441-3451. doi:10.1038/sj.emboj.7600349
[31] J. J. Wilson and R. A. Kovall, “Crystal Structure of the CSL-Notch-Mastermind Ternary Complex Bound to DNA,” Cell, Vol. 124, No. 5, 2006, pp. 985-996. doi:10.1016/j.cell.2006.01.035
[32] A. S. Weinmann, et al., “Use of Chromatin Immunoprecipitation to Clone Novel E2F Target Promoters,” Molecular and Cellular Biology, Vol. 21, No. 20, 2001, pp. 6820-6832. doi:10.1128/MCB.21.20.6820-6832.2001
[33] D. T. Nellesen, E.C. Lai and J.W. Posakony, “Discrete Enhancer Elements Mediate Selective Responsiveness of Enhancer of Split Complex Genes to Common Transcriptional Activators,” Developmental Biology, Vol. 213, No. 1, 1999, pp. 33-53. doi:10.1006/dbio.1999.9324
[34] A. M. Bailey and J. W. Posakony, “Suppressor of Hairless Directly Activates Transcription of Enhancer of Split Complex Genes in Response to Notch Receptor Activity,” Genes and Development, Vol. 9, No. 21, 1995, pp. 2609-2622. doi:10.1101/gad.9.21.2609
[35] S. Jeffries, D. J. Robbins and A. J. Capobianco, “Characterization of a High-Molecular-Weight Notch Complex in the Nucleus of Notch(ic)-Transformed RKE Cells and in a Human T-Cell Leukemia Cell Line,” Molecular and Cellular Biology, Vol. 22, No. 11, 2002, pp. 3927-3241. doi:10.1128/MCB.22.11.3927-3941.2002
[36] D. R. Friedmann, J. J. Wilson and R. A. Kovall, “RAM-Induced Allostery Facilitates Assembly of a Notch Pathway Active Transcription Complex,” The Journal of Biological Chemistry, Vol. 283, No. 21, 2008, pp. 14781-14791. doi:10.1074/jbc.M709501200
[37] R. A. Kovall, “Structures of CSL, Notch and Mastermind Proteins: Piecing Together an Active Transcription Complex,” Current Opinion in Structural Biology, Vol. 17, No. 1, 2007, pp. 117-127. doi:10.1016/j.sbi.2006.11.004
[38] M. Fried and D. M. Crothers, “Equilibria and Kinetics of Lac Repressor-Operator Interactions by Polyacrylamide Gel Electrophoresis,” Nucleic Acids Research, Vol. 9, No. 23, 1981, pp. 6505-6525. doi:10.1093/nar/9.23.6505
[39] A. S. McElhinny, J. L. Li and L. Wu, “Mastermind-Like Transcriptional Co-Activators: Emerging Roles in Regulating Cross Talk among Multiple Signaling Pathways,” Oncogene, Vol. 27, No. 38, 2008, pp. 5138-5147. doi:10.1038/onc.2008.228
[40] N. Yamamoto, et al., “Role of Deltex-1 as a Transcriptional Regulator Downstream of the Notch Receptor,” The Journal of Biological Chemistry, Vol. 276, No. 48, 2001, pp. 45031-45040. doi:10.1074/jbc.M105245200
[41] J. W. Cave, et al., “A DNA Transcription Code for Cell-Specific Gene Activation by Notch Signaling,” Current Biology, Vol. 15, No. 2, 2005, pp. 94-104. doi:10.1016/j.cub.2004.12.070
[42] A. Neves and J. R. Priess, “The REF-1 Family of bHLH Transcription Factors Pattern C. elegans Embryos through Notch-Dependent and Notch-Independent Pathways,” Developmental Cell, Vol. 8, No. 6, 2005, pp. 867-879. doi:10.1016/j.devcel.2005.03.012
[43] L. M. Persson and A. C. Wilson, “Wide-Scale Use of Notch Signaling Factor CSL/RBP-Jkappa in RTA-Mediated Activation of Kaposi’s Sarcoma-Associated Herpesvirus Lytic Genes,” Journal of Virology, Vol. 84, No. 3, 2009, pp. 1334-1347. doi:10.1128/JVI.01301-09
[44] H. Hamidi, et al., “Identification of Novel Targets of CSL-Dependent Notch Signaling in Hematopoiesis,” PLoS ONE, Vol. 6, No. 5, 2011, p. e20022. doi:10.1371/journal.pone.0020022
[45] S. Zhou, et al., “SKIP, a CBF1-Associated Protein, Interacts with the Ankyrin Repeat Domain of NotchIC to Facilitate NotchIC Function,” Molecular and Cellular Biology, Vol. 20, No. 7, 2000, pp. 2400-2410. doi:10.1128/MCB.20.7.2400-2410.2000
[46] A. Krejci and S. Bray, “Notch Activation Stimulates Transient and Selective Binding of Su(H)/CSL to Target Enhancers,” Genes & Development, Vol. 21, No. 11, 2007, pp. 1322-1327. doi:10.1101/gad.424607
[47] Y. Nam, et al., “Cooperative Assembly of Higher-Order Notch Complexes Functions as a Switch to Induce Transcription,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 7, 2007, pp. 2103-2108. doi:10.1073/pnas.0611092104

  
comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.