As described in Chapter 6, transcription factors are essential for the process of eukaryotic transcription, binding to specific DNA sequences and then acting to either activate or repress transcription of the target gene. Such transcription factors play a central role in regulating gene transcription. As described in Chapter 1 (Section 1.5), transcription is the key stage at which gene expression is regulated to produce different cell types and tissues or to allow cells to respond to specific stimuli.
Multiple-choice questions
Questions for Discussion
- Despite having identical receptors, different cells of a multicellular organism respond differently to the same signaling molecule. Discuss the molecular mechanisms that enable differential outcomes to the same signaling ligand.
- Signaling proteins can be activated through different mechanisms, including post-translational modifications such as phosphorylation and protein-protein interactions. Discuss why phosphorylation and dephosphorylation play a prominent role in turning signaling proteins on and off as compared to other mechanisms, like small molecule binding via allosteric sites.
- Explain how exposure to certain environmental stressors can create cellular memory to develop resistance or tolerance to that particular stress.
- Plants and animals independently evolved multicellularity. However, several signaling proteins and second messengers are conserved. Discuss the similarities and differences in signaling pathways between plants and animals.
- The AKT-mTOR pathway is central to bridging metabolism and gene expression. Discuss the role of this pathway in modifying chromatin structure to control gene expression in response to hyperglycemia.
Further Reading
10.1 Regulation of transcription factor activity by ligands which enter the cell
Girgenti, M. J., Pothula, S., & Newton, S. S. (2021). Stress and Its Impact on the Transcriptome. Biological Psychiatry, 90(2), 102–108. https://doi.org/10.1016/j.biopsych.2020.12.011
Gomez-Pastor, R., Burchfiel, E. T., & Thiele, D. J. (2018). Regulation of heat shock transcription factors and their roles in physiology and disease. Nature Reviews. Molecular Cell Biology, 19(1), 4–19. https://doi.org/10.1038/nrm.2017.73
Hackley, R. K., & Schmid, A. K. (2019). Global Transcriptional Programs in Archaea Share Features with the Eukaryotic Environmental Stress Response. Journal of Molecular Biology, 431(20), 4147–4166. https://doi.org/10.1016/j.jmb.2019.07.029
Hernández-Elvira, M., & Sunnerhagen, P. (2022). Post-transcriptional regulation during stress. FEMS Yeast Research, 22(1), foac025. https://doi.org/10.1093/femsyr/foac025
Johnson, H. M., Noon-Song, E., & Ahmed, C. M. (2019). Noncanonical IFN Signaling, Steroids, and STATs: A Probable Role of V-ATPase. Mediators of Inflammation, 2019, 4143604. https://doi.org/10.1155/2019/4143604
Kainth, A. S., Chowdhary, S., Pincus, D., & Gross, D. S. (2021). Primordial super-enhancers: Heat shock-induced chromatin organization in yeast. Trends in Cell Biology, 31(10), 801–813. https://doi.org/10.1016/j.tcb.2021.04.004
Kmiecik, S. W., & Mayer, M. P. (2022). Molecular mechanisms of heat shock factor 1 regulation. Trends in Biochemical Sciences, 47(3), 218–234. https://doi.org/10.1016/j.tibs.2021.10.004
Liu, Z., Hu, Q., & Rosenfeld, M. G. (2014). Complexity of the RAR-mediated transcriptional regulatory programs. Sub-Cellular Biochemistry, 70, 203–225. https://doi.org/10.1007/978-94-017-9050-5_10
Sedano, M. J., Harrison, A. L., Zilaie, M., Das, C., Choudhari, R., Ramos, E., & Gadad, S. S. (2020). Emerging Roles of Estrogen-Regulated Enhancer and Long Non-Coding RNAs. International Journal of Molecular Sciences, 21(10), 3711. https://doi.org/10.3390/ijms21103711
10.2 Regulation of transcription factor activity by phosphorylation induced by extracellular signaling molecules
Capece, D., Verzella, D., Flati, I., Arboretto, P., Cornice, J., & Franzoso, G. (2022). NF-κB: Blending metabolism, immunity, and inflammation. Trends in Immunology, 43(9), 757–775. https://doi.org/10.1016/j.it.2022.07.004
Cramer, P. (2019). Organization and regulation of gene transcription. Nature, 573(7772), 45–54. https://doi.org/10.1038/s41586-019-1517-4
From genoprotection to rejuvenation—PubMed. (n.d.). Retrieved February 18, 2024, from https://pubmed.ncbi.nlm.nih.gov/33049666/
Massagué, J., & Sheppard, D. (2023). TGF-β signaling in health and disease. Cell, 186(19), 4007–4037. https://doi.org/10.1016/j.cell.2023.07.036
Nosella, M. L., & Forman-Kay, J. D. (2021). Phosphorylation-dependent regulation of messenger RNA transcription, processing and translation within biomolecular condensates. Current Opinion in Cell Biology, 69, 30–40. https://doi.org/10.1016/j.ceb.2020.12.007
Steven, A., Friedrich, M., Jank, P., Heimer, N., Budczies, J., Denkert, C., & Seliger, B. (2020). What turns CREB on? And off? And why does it matter? Cellular and Molecular Life Sciences: CMLS, 77(20), 4049–4067. https://doi.org/10.1007/s00018-020-03525-8
Williams, L. M., & Gilmore, T. D. (2020). Looking Down on NF-κB. Molecular and Cellular Biology, 40(15), e00104-20. https://doi.org/10.1128/MCB.00104-208.3
10.3 Regulation of transcription factor activity by other post-translational modifications
Emanuele, M. J., Enrico, T. P., Mouery, R. D., Wasserman, D., Nachum, S., & Tzur, A. (2020). Complex Cartography: Regulation of E2F Transcription Factors by Cyclin F and Ubiquitin. Trends in Cell Biology, 30(8), 640–652. https://doi.org/10.1016/j.tcb.2020.05.002
Fiorini, G., & Schofield, C. J. (2024). Biochemistry of the hypoxia-inducible factor hydroxylases. Current Opinion in Chemical Biology, 79, 102428. https://doi.org/10.1016/j.cbpa.2024.102428
Goldman, N., Chandra, A., & Vahedi, G. (2021). Transcription factors combine to paint the methylation landscape. Trends in Immunology, 42(12), 1060–1062. https://doi.org/10.1016/j.it.2021.10.011
Millán-Zambrano, G., Burton, A., Bannister, A. J., & Schneider, R. (2022). Histone post-translational modifications—Cause and consequence of genome function. Nature Reviews. Genetics, 23(9), 563–580. https://doi.org/10.1038/s41576-022-00468-7
Pellegrino, N. E., Guven, A., Gray, K., Shah, P., Kasture, G., Nastke, M.-D., Thakurta, A., Gesta, S., Vishnudas, V. K., Narain, N. R., & Kiebish, M. A. (2022). The Next Frontier: Translational Development of Ubiquitination, SUMOylation, and NEDDylation in Cancer. International Journal of Molecular Sciences, 23(7), 3480. https://doi.org/10.3390/ijms23073480
Squair, D. R., & Virdee, S. (2022). A new dawn beyond lysine ubiquitination. Nature Chemical Biology, 18(8), 802–811. https://doi.org/10.1038/s41589-022-01088-2
Talamillo, A., Barroso-Gomila, O., Giordano, I., Ajuria, L., Grillo, M., Mayor, U., & Barrio, R. (2020). The role of SUMOylation during development. Biochemical Society Transactions, 48(2), 463–478. https://doi.org/10.1042/BST201903908.4
10.4 Regulation of transcription factor activity by signals which regulate precursor processing
Ingham, P. W. (2022). Hedgehog signaling. Current Topics in Developmental Biology, 149, 1–58. https://doi.org/10.1016/bs.ctdb.2022.04.003
McIntyre, B., Asahara, T., & Alev, C. (2020). Overview of Basic Mechanisms of Notch Signaling in Development and Disease. Advances in Experimental Medicine and Biology, 1227, 9–27. https://doi.org/10.1007/978-3-030-36422-9_2
Sprinzak, D., & Blacklow, S. C. (2021). Biophysics of Notch Signaling. Annual Review of Biophysics, 50(1), 157–189. https://doi.org/10.1146/annurev-biophys-101920-082204
Walton, K. D., & Gumucio, D. L. (2021). Hedgehog Signaling in Intestinal Development and Homeostasis. Annual Review of Physiology, 83, 359–380. https://doi.org/10.1146/annurev-physiol-031620-094324
10.5 Regulation of histone modification and chromatin structure by cellular signaling pathways
Dupont, S., & Wickström, S. A. (2022). Mechanical regulation of chromatin and transcription. Nature Reviews. Genetics, 23(10), 624–643. https://doi.org/10.1038/s41576-022-00493-6
Gapa, L., Alfardus, H., & Fischle, W. (2022). Unconventional metabolites in chromatin regulation. Bioscience Reports, 42(1), BSR20211558. https://doi.org/10.1042/BSR20211558
Morrison, A. J. (2020). Chromatin-remodeling links metabolic signaling to gene expression. Molecular Metabolism, 38, 100973. https://doi.org/10.1016/j.molmet.2020.100973
Villaseñor, R., & Baubec, T. (2021). Regulatory mechanisms governing chromatin organization and function. Current Opinion in Cell Biology, 70, 10–17. https://doi.org/10.1016/j.ceb.2020.10.015
10.6 Regulation of post-transcriptional processes by cellular signaling pathways
Angarola, B. L., & Anczuków, O. (2021). Splicing alterations in healthy aging and disease. Wiley Interdisciplinary Reviews. RNA, 12(4), e1643. https://doi.org/10.1002/wrna.1643
Bushell M, Stoneley M, Spriggs K.A. & Willis A.E. (2008) SF2/ASF TORCs up translation. Mol Cell 30:262–263.
Carpenter, S., Ricci, E. P., Mercier, B. C., Moore, M. J., & Fitzgerald, K. A. (2014). Post-transcriptional regulation of gene expression in innate immunity. Nature Reviews. Immunology, 14(6), 361–376. https://doi.org/10.1038/nri3682
Horman S.R., Janas M.M., Litterst C et al. (2013) Akt-mediated phosphorylation of Argonaute 2 downregulates cleavage and upregulates translational repression of microRNA targets. Mol Cell 50:356–367.
Shimobayashi M & Hall M.N. (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15:155–162.