Preprint / Version 1

How Cell Cycle Transcription Factors Inhibit Neural Proliferation

##article.authors##

  • Auburne Mauger Polygence

DOI:

https://doi.org/10.58445/rars.318

Keywords:

Neuron, Cell Cycle Arrest, Transcription Factor, Apoptosis, G0 Phase, Anti-proliferation, CDK Inhibition

Abstract

Adult neurons are incapable of cellular proliferation due to their abnormal cell cycle. Upon maturation, post-mitotic neurons face terminal cell cycle arrest at the G1/S checkpoint. If cell cycle re-entry is attempted, neurons trigger pro-apoptotic pathways that kill the cell before any proliferative progress can be made (Figure 1). These processes inhibiting neural replication are highly influenced by cell cycle transcription factors, which face neuro-specific regulations to induce such unique cellular events. This paper examines how the regulations and differential functions of neural cell cycle transcription factors facilitate neurons’ inability to proliferate. Specifically, we review how BHLH, E2F, SMAD, FOXO1, SP1, c-MYC, p53, and Brn-3a regulate cell cycle arrest, and how E2F1, FOXO1, C-JUN, and p53 facilitate neural apoptosis upon attempted cell cycle re-entry.  

References

Alberts, B., Johnson, A., & Lewis, J. (2002). An Overview of the Cell Cycle. Molecular Biology of the Cell, 4. https://www.ncbi.nlm.nih.gov/books/NBK26869/

Bertoli, C., Skotheim, J. M., & Bruin, R. A. M. (2015). Control of Cell Cycle Transcription during G1 and S Phases. Nature Reviews Molecular Cell Biology, 14(8), 518–528. https://doi.org/10.1038%2Fnrm3629

Galderisi, U., Paolo Jori, F., & Giordano, A. (2003). Cell Cycle Regulation and Neural Differentiation. Oncogene, 22, 5208–5219. https://dpl6hyzg28thp.cloudfront.net/media/cell_cycle_regulation_and_neural_differentiation_2003.pdf

Creff, J., & Besson, A. (2020). Functional Versatility of the CDK Inhibitor p57Kip2. Cell Growth and Division, 8. https://doi.org/10.3389/fcell.2020.584590

Greene, L. A., Biswas, S. C., & Liu, D. X. (2003). Cell cycle molecules and vertebrate neuron death: E2F at the hub. Cell Death & Differentiation, 11, 49–60. https://doi.org/10.1038/sj.cdd.4401341

García-Campmany, L., & Martí, E. (2007). The TGFbeta intracellular effector Smad3 regulates neuronal differentiation and cell fate specification in the developing spinal cord. Development, 134(1), 65–75. https://doi.org/10.1242/dev.02702

Ochocinska, M. J., & Hitchcock, P. F. (2009). NeuroD regulates proliferation of photoreceptor progenitors in the retina of the zebrafish. Mechanisms of development, 126(3-4), 128–141. https://doi.org/10.1016/j.mod.2008.11.009

Uittenbogaard, M., & Chiaramello, A. (2006). The basic helix-loop-helix transcription factor Nex-1/Math-2 promotes neuronal survival of PC12 cells by modulating the dynamic expression of anti-apoptotic and cell cycle regulators. Journal of Neurochemistry, 92(3), 585–596. https://doi.org/10.1111%2Fj.1471-4159.2004.02886.x

Vandussen, K. L., & Samuelson, L. C. Mouse atonal homolog 1 directs intestinal progenitors to secretory cell rather than absorptive cell fate. Developmental Biology, 346(2), 215-223. https://doi.org/10.1016/j.ydbio.2010.07.026

Skaggs, K., Martin, D. M., & Novitch, B. G. (2011). Regulation of spinal interneuron development by the Olig-related protein Bhlhb5 and Notch signaling. Development, 138 (15), 3199–3211.https://doi.org/10.1242/dev.057281

Lacomme, M., Liaubet, L., Pituello, F., Bel-Vialar, S. (2012). NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G1 and S Phases of the Cell Cycle. Molecular Cell Biology, 32(13), 2596–2607. https://doi.org/10.1128%2FMCB.06745-11

Somnay, Y. R., Zarebczan Dull, B., Eide, J., Jaskula-Sztul, R., & Chen, H. (2015). Chrysin suppresses the achaete-scute complex-like1 and alters the neuroendocrine phenotype of carcinoids. Cancer Gene Therapy, 22(10), 496–505. https://doi.org/10.1038%2Fcgt.2015.49

Bertrand, N., Castro, D. S., Guillemot, F. (2002). Nature Reviews, 3, 517-529. http://www.bio.brandeis.edu/classes/nbio143/Papers/Neurogenesis/Bertrandetal.pdf

Lécuyer, E., Larivière, S., Sincennes, M., Haman, A., Lahlil, R., Todorova,M., Tremblay, M., Wilkes, B. C., Hoang,T. (2007). Protein Stability and Transcription Factor Complex Assembly Determined by the SCL-LMO2 Interaction. Journal of Biological Chemistry, 282(46), 33649-33658. https://doi.org/10.1074/jbc.M703939200

Yan, C. H., Levesque, M., Claxton, S., Johnson, R. L., & Ang, S. (2011). Lmx1a and Lmx1b Function Cooperatively to Regulate Proliferation, Specification, and Differentiation of Midbrain Dopaminergic Progenitors. Journal of Neuroscience, 31 (35), 12413-12425. https://doi.org/10.1523/JNEUROSCI.1077-11.2011

Yoshikawa, K. (2000). Cell cycle regulators in neural stem cells and postmitotic neurons. Neuroscience Research, 37, 1-14. https://dpl6hyzg28thp.cloudfront.net/media/cell_cycle_regulators_in_neurons.pdf

Giangrande, P. H., Zhu, W. Schlisio, S., Sun, X., Mori, S., Gaubatz, S., & Nevins, J. R. (2004). A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription. Genes & Development, 18, 2941-2951, http://www.genesdev.org/cgi/doi/10.1101/gad.1239304

Palazuelos, J., Kilngener, M., & Aguirre, A. (2014). TGF Signaling Regulates the Timing of CNS Myelination by Modulating Oligodendrocyte Progenitor Cell Cycle Exit through SMAD3/4/FoxO1/Sp1. The Journal of Neuroscience, 34(23), 7917–7930. https://www.jneurosci.org/content/jneuro/34/23/7917.full.pdf Palazuelos, J., Kilngener, M., & Aguirre, A. (2014). TGF Signaling Regulates the Timing of CNS Myelination by Modulating Oligodendrocyte Progenitor Cell Cycle Exit through SMAD3/4/FoxO1/Sp1. The Journal of Neuroscience, 34(23), 7917–7930. https://www.jneurosci.org/content/jneuro/34/23/7917.full.pdf

Kim, A. H., & Bonni A. (2008). Cell Cycle, 7(24), 3819-3822. https://doi.org/10.4161/cc.7.24.7215

Liang, YY., Brunicardi, F. & Lin, X. (2009). Smad3 mediates immediate early induction of Id1 by TGF-β. Cell Research,19, 140–148. https://doi.org/10.1038/cr.2008.321

Lu, J., Wu, Y., Sousa, N., & Almeida, O. F. (2005). SMAD pathway mediation of BDNF and TGF beta 2 regulation of proliferation and differentiation of hippocampal granule neurons. Development, 132(14), 3231–3242. https://doi.org/10.1242/dev.01893

Ullah, I., Sun, W., Tang, L., & Feng, J. (2018). Roles of Smads Family and Alternative Splicing Variants of Smad4 in Different Cancers. Journal of Cancer, 9(21), 4018–4028. https://doi.org/10.7150%2Fjca.20906

Hester, M., Thompson, J. C., Mills, J., Liu, Y., El-Hodiri, H. M., & Weinstein, M. (2005). Smad1 and Smad8 function similarly in mammalian central nervous system development. Molecular and cellular biology, 25(11), 4683–4692. https://doi.org/10.1128/MCB.25.11.4683-4692.2005

Xie, Z., Chen, Y., Li, Z., Bai, G., Zhu, Y., Yan, R., Tan, F., Chen, Y., Guillemot, F., Li, L., & Jing, N. (2011). Smad6 promotes neuronal differentiation in the intermediate zone of the dorsal neural tube by inhibition of the Wnt/β-catenin pathway. PNAS, 108(29), 12119–12124. https://doi.org/10.1073%2Fpnas.1100160108

Weizmann Institute of Science. (2023). SMAD2 Gene - SMAD Family Member 2. GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=SMAD2&keywords=SMAD2

Weizmann Institute of Science. (2023). SMAD3 Gene - SMAD Family Member 3. GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=SMAD3&keywords=SMAD2

Krampert, M., Chirasani, S. R., Wachs, F., Aigner, R., Bogdahn, U., Yingling, J. M., Heldin, C., Aigner, L., & Heuchel, R. (2010). Smad7 Regulates the Adult Neural Stem/Progenitor Cell Pool in a Transforming Growth Factor β- and Bone Morphogenetic Protein-Independent Manner. Molecular and Cellular Biology, 30(14), 3685–3694. https://doi.org/10.1128%2FMCB.00434-09

Tedeschi, A., & Giovanni, S. D. (2009). The non-apoptotic role of p53 in neuronal biology: enlightening the dark side of the moon. EMBO Reports, 10(6), 576–583. https://doi.org/10.1038%2Fembor.2009.89

Chen, J. (2016). The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. Cold Spring Harbor Perspectives in Medicine, 6(3). https://doi.org/10.1101%2Fcshperspect.a026104

Kumar, P., Naumann, U., Aigner, L., Wischhusen, J., Beier, C. P., & Beier, D. (2015). Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53. American Journal of Cancer Research, 5(11), 3436–3445. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697689/

P13405 · RB_MOUSE. (n.d.) UniProt. Retrieved August 2, 2023, from https://www.uniprot.org/uniprotkb/P13405/entry#sequences

P25233 · NECD_MOUSE. (n.d.) UniProt. Retrieved August 2, 2023, from https://www.uniprot.org/uniprotkb/P25233/entry#structure

Miller, F. D., Pozniak, C. D., & Walsh, G.S. (2000). Neuronal life and death: an essential role for the p53 family. Cell Death & Differentiation, 7, 880-888. https://doi.org/10.1038/sj.cdd.4400736

Gilley, J., Coffer, P. J., & Ham, J. (2003). FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. The Journal of Cell Biology, 162(4), 613-622. http://www.jcb.org/cgi/doi/10.1083/jcb.200303026

Frade, J. M., & Ovejero-Benito, M. C. (2015). Neuronal cell cycle: the neuron itself and its circumstances. Cell Cycle, 14(5), 712–720. https://doi.org/10.1080%2F15384101.2015.1004937

Estus, S., Zaks, W. J., Freeman, R. S., Gruda, M., Bravo, R., & Johnson, E. M. Jr. (1994). Altered Gene Expression in Neurons during Programmed Cell Death: Identification of c-jun as Necessary for Neuronal Apoptosis. The Journal of Cell Biology, 23(6), 1717-1727. https://rupress.org/jcb/article-pdf/127/6/1717/1264468/1717.pdf

Bashari, D., Hacohen, D., Ginsberg, D. (2011). JNK activation is regulated by E2F and promotes E2F1-induced apoptosis. Cellular Signaling, 23(1), 65-70. https://www.sciencedirect.com/science/article/abs/pii/S0898656810002317

Reddy, C. E., Albanito, L., De Marco, P., Aiello, D., Maggiolini, M., Napoli, A., & Musti, A. M. (2013). Multisite phosphorylation of c-Jun at threonine 91/93/95 triggers the onset of c-Jun pro-apoptotic activity in cerebellar granule neurons. Cell Death and Disease, 4. https://doi.org/10.1038/cddis.2013.381

Hershko, T., Chaussepied, M., Oren, M., & Ginsberg, D. (2005). Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F. Cell death and differentiation, 12(4), 377–383. https://doi.org/10.1038/sj.cdd.4401575

Wang, D. B., Kinoshita, C., Kinoshita, Y., & Morrison, R. S. (2015). p53 and Mitochondrial Function in Neurons. Biochimica et Biophysica Acta, 1842(8), 1186-1197. https://doi.org/10.1016/j.bbadis.2013.12.015

Nakamizo, A., Amano, T., Zhang, W., Zhang, X., Ramadas, L., Liu, T., Bekele, B. N., Shono, T., Sasaki, T., Benedict, W. F., Sawaya, R., & Lang, F. F. (2008) Phosphorylation of Thr18 and Ser20 of p53 in Ad-p53–induced apoptosis. Neuro-Oncology, 10(3), 275–291. https://doi.org/10.1215/15228517-2008-015

Yogosawa, S., & Yoshida, K. (2018). Tumor suppressive role for kinases phosphorylating p53 in DNA damage‐induced apoptosis. Cancer Science, 109(11), 3376–3382. https://doi.org/10.1111%2Fcas.13792

Thompson, T., Tovar, C., Yang, H., Carvajal, D., Vu, B. T., Xu, Q., Wahl, G. M., Heimbrook, D. C., & Vassilev, L. T. (2004). Phosphorylation of p53 on Key Serines Is Dispensable for Transcriptional Activation and Apoptosis. Protein Synthesis, Post-Translational Modification, and Degradation, 279(51), 53015-53022. https://doi.org/10.1074/jbc.M410233200

Loughery, J., Cox, M., Smith, L. M., & Meek, D. W. (2014). Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters. Nucleic Acids Research, 42(12), 7666–7680. https://doi.org/10.1093/nar/gku501

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2023-08-11