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Gene regulation in the immediate-early response process
Open accessAbstract
Immediate-early genes (IEGs) can be activated and transcribed within minutes after stimulation, without the need for de novo protein synthesis, and they are stimulated in response to both cell-extrinsic and cell-intrinsic signals. Extracellular signals are transduced from the cell surface, through receptors activating a chain of proteins in the cell, in particular extracellular-signal-regulated kinases (ERKs), mitogen-activated protein kinases (MAPKs) and members of the RhoA-actin pathway. These communicate through a signaling cascade by adding phosphate groups to neighboring proteins, and this will eventually activate and translocate TFs to the nucleus and thereby induce gene expression. The gene activation also involves proximal and distal enhancers that interact with promoters to simulate gene expression. The immediate-early genes have essential biological roles, in particular in stress response, like the immune system, and in differentiation. Therefore they also have important roles in various diseases, including cancer development. In this paper we summarize some recent advances on key aspects of the activation and regulation of immediate-early genes.
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“these are known to regulate neuronal activity and inflammatory responses under stress conditions”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [45]
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“They are believed to be crucial for synaptic plasticity, hippocampal memory, and long-term changes in mood.(59) Decreased hippocampal IEGs expression by infusion of antisense oligonucleotide has been reported to impair learning and memory.”
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“…(also known as ZiF268), are a class of genes that is activated transiently and rapidly in response to a wide variety of cellular stimuli (Hunt et al., 1988; Sagar et al., 1988; Kaczmarek and Nikolajew, 1990; Hughes et al., 1992; Pinaud, 2004; Terleph and Tremere, 2006; Bahrami and Drabløs, 2016).”
BackgroundReshetnikov, V. V., Kisaretova, P. E., Ershov, N., Merkulova, T. I., & Bondar, N. P. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110068 · Cited by 42
Majcher‐Maślanka, I., Solarz, A., Wędzony, K., & Chocyk, A. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.03.038 · Cited by 35
Morgan, D., Berggren, K. L., Spiess, C., Smith, H. M., Tejwani, A., Weir, S. J., Lominska, C. E., Thomas, S. M., & Gan, G. N. (2021) · Molecular Carcinogenesis · doi:10.1002/mc.23348 · Cited by 42
“Many of these genes are transcription factors themselves and they activate genes involved in changes to the cell cycle, cell growth, cell differentiation, apoptosis, and the immune response.(134,135) Heidenreich et al.”
BackgroundBegni, V., Sanson, A., Luoni, A., Sensini, F., Grayson, B., Munni, S., Neill, J. C., & Riva, M. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084119 · Cited by 36
“The 60 min time period was chosen based on previous studies, and since immediate-early genes are rapidly induced [7,52].”
MethodInitiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory
Kaldun, J. C., & Sprecher, S. G. (2019) · BioEssays · doi:10.1002/bies.201900045 · Cited by 50
Li, X., García-Elías, A., Benito, B., & Nattel, S. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab035 · Cited by 39
“Activation of G proteins and kinases activates ERK2 and JNK1 and leads to the phosphorylation of the early response genes c-Jun, c-Fos, and Fra-1.”
BackgroundMa’ayeh, S. Y., Knörr, L., Sköld, K., Garnham, A. L., Ansell, B. R. E., Jex, A. R., & Svärd, S. G. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00244 · Cited by 40
“Control Primary Response Genes Primary response genes, which include immediate early and delayed genes, play pivotal roles in a wide range of biological processes including differentiation, proliferation, survival, stress, innate and adaptive immune responses, and glucose metabolism (Fowler et al., 2011; Bahrami and D…”
BackgroundRNA polymerase II pausing in development: orchestrating transcription
Abuhashem, A., Garg, V., & Hadjantonakis, A. (2022) · Open Biology · doi:10.1098/rsob.210220 · Cited by 38
“This mechanism of gene regulation seems plausible given that many transcriptional responses occur within minutes of signal induction [112,113].”
BackgroundSommerlandt, F. M. J., Brockmann, A., Rössler, W., & Spaethe, J. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2948-z · Cited by 33
Multivariate Control of Transcript to Protein Variability in Single Mammalian Cells
Popovic, D., Koch, B., Kueblbeck, M., Ellenberg, J., & Pelkmans, L. (2018) · Cell Systems · doi:10.1016/j.cels.2018.09.001 · Cited by 33
IER2-induced senescence drives melanoma invasion through osteopontin
Kyjacová, L., Saup, R., Rönsch, K., Wallbaum, S., Dukowic‐Schulze, S., Foss, A., Scherer, S. D., Rothley, M., Neeb, A., Grau, N., et al. (2021) · Oncogene · doi:10.1038/s41388-021-02027-6 · Cited by 38
Tran, C., Heng, B., Teo, J. D., Humphrey, S. J., Qi, Y., Couttas, T. A., Stefen, H., Brettle, M., Fath, T., Guillemin, G. J., et al. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14917 · Cited by 34
“Similarly, only JTE significantly reduced JUN phosphorylation at S63 in both U251 cells and primary astrocytes (Figure 5c,d).”
BackgroundMethodInfluentialBrazier-Hicks, M., Howell, A., Cohn, J., Hawkes, T., Hall, G., Mcindoe, E., & Edwards, R. (2019) · Journal of Experimental Botany · doi:10.1093/jxb/erz438 · Cited by 32
“do not require protein synthesis and so their expression is not affected by translational inhibitors (Bahrami and Drabløs, 2016).”
BackgroundZhang, Y., Alexander Joel Federation, Kim, S., O’Keefe, J., Lun, M., Xiang, D., Brown, J. D., & Steinhauser, M. L. (2018) · Journal of Clinical Investigation · doi:10.1172/jci98353 · Cited by 42
Environmental perturbations lead to extensive directional shifts in RNA processing
Richards, A. L., Watza, D., Findley, A. S., Alazizi, A., Wen, X., Pai, A. A., Piqué-Regi, R., & Luca, F. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006995 · Cited by 31
Geng, H., Lafon, G., Avarguès-Weber, A., Buatois, A., Massou, I., & Giurfa, M. (2022) · Communications Biology · doi:10.1038/s42003-022-03075-8 · Cited by 29
Pubertal adversity alters chromatin dynamics and stress circuitry in the pregnant brain
Morrison, K. E., Cole, A. B., Kane, P. J., Meadows, V. E., Thompson, S. M., & Bale, T. L. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0634-y · Cited by 23
Oshigiri, T., Sasaki, T., Sasaki, M., Kataoka-Sasaki, Y., Nakazaki, M., Oka, S., Morita, T., Hirota, R., Yoshimoto, M., Yamashita, T., et al. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.5793 · Cited by 28
Gracey, A. Y., & Connor, K. M. (2016) · Marine Genomics · doi:10.1016/j.margen.2016.07.004 · Cited by 34
“…are broadly classified as early genes (Reinke et al., 2013), a class of genes that are activated and transcribed within minutes of various stimuli (Bahrami and Drablos, 2016), 2 apoptosis-inhibiting baculoviral inhibitor of apoptosis (IAP) repeat-containing proteins (BIRC2, BIRC7), and 2 isoforms…”
BackgroundDirection of epithelial folding defines impact of mechanical forces on epithelial state
Błoński, S., Aureille, J., Badawi, S., Zaremba, D., Pernet, L., Grichine, A., Fraboulet, S., Korczyk, P. M., Recho, P., Guilluy, C., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.11.008 · Cited by 29
Wang, L., Tran, A., Lee, J., & Belsham, D. D. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110991 · Cited by 33
Regulation of Cell Cycle Entry and Exit: A Single Cell Perspective
Coller, H. A. (2019) · Comprehensive physiology · doi:10.1002/cphy.c190014 · Cited by 33
“The transcription factor Myc is also induced as an immediate early gene (18).”
Naderi, M., Ferrari, M. C. O., Chivers, D. P., & Niyogi, S. (2018) · Environmental Science & Technology · doi:10.1021/acs.est.8b04768 · Cited by 32
Kim, J., Ko, M. J., Gonzales, E. L., Kang, R. J., Kim, D. G., Kim, Y., Seung, H., Oh, H. A., Eun, P. H., & Shin, C. Y. (2018) · Scientific Reports · doi:10.1038/s41598-018-30524-4 · Cited by 29
Rose, S. J., Pack, T., Peterson, S. M., Payne, K., Borrelli, E., & Caron, M. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.254 · Cited by 27
Peripheral neuronal activation shapes the microbiome and alters gut physiology
Griffiths, J. A., Yoo, B. B., Thuy-Boun, P. S., Cantu, V., Weldon, K. C., Challis, C., Sweredoski, M. J., Chan, K. Y., Thron, T., Sharon, G., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113953 · Cited by 37
Morsey, B., Niu, M., Dyavar, S. R., Fletcher, C. V., Lamberty, B. G., Emanuel, K., Fangmeier, A., & Fox, H. S. (2021) · iScience · doi:10.1016/j.isci.2021.102357 · Cited by 25
Feeling the force from within – new tools and insights into nuclear mechanotransduction
Morival, J. L. P., Hazelwood, A., & Lammerding, J. (2025) · Journal of Cell Science · doi:10.1242/jcs.263615 · Cited by 26
The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases
He, Y., Zhou, H., Chen, L., Wang, Y., Xie, W., Xu, Z., Xiong, Y., Feng, Y., Liu, G.-Y., Li, X., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.954744 · Cited by 33
“In cells, AP-1 family members, including Fra-1, belong to immediate early cell genes (48).”
BackgroundAn Adaptive Role for DNA Double-Strand Breaks in Hippocampus-Dependent Learning and Memory
Boutros, S. W., Unni, V. K., & Raber, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158352 · Cited by 31
“Expression of IEGs is cleared relatively quickly, returning to baseline levels within 2–3 h following stimulation [11].”
BackgroundDutta, M., Saha, A., Moin, M., & Kirti, P. (2021) · Frontiers in Plant Science · doi:10.3389/fpls.2021.777285 · Cited by 25
β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery
Leven, P., Schneider, R., Schneider, L. H., Mallesh, S., Berghe, P. V., Sasse, P., Kalff, J. C., & Wehner, S. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02937-0 · Cited by 29
“Regarding gliosis, we detected an upregulation of Ier5l and Ifrd1 , two genes of the “immediate-early gene” group that regulate cell growth and immune function [57] and include other factors., e.g., Fos , Egr1/2 , Nr4a1/2 , Jun , Atf3, and Fosl , all strongly induced upon IM.”
BackgroundLohani, N., Singh, M. B., & Bhalla, P. (2022) · Frontiers in Plant Science · doi:10.3389/fpls.2022.905674 · Cited by 24
Thorstensen, M., Turko, A., Heath, D., Jeffries, K., & Pitcher, T. (2022) · bioRxiv · doi:10.1101/2022.02.20.481219 · Cited by 24
“The panel of early response genes represents a positive control of genes we expected would change in expression if the thermal and handling stressors were reflected in a transcriptomic response (Bahrami and Drabløs, 2016; Fowler et al., 2011; Jeffries et al., 2018; Sopinka et al., 2016).”
Duke, C. G., Savell, K. E., Tuscher, J., Phillips, R. A., & Day, J. (2019) · eNeuro · doi:10.1523/eneuro.0386-19.2019 · Cited by 24
Glucocorticoids delay RAF-induced senescence promoted by EGR1
Carvalho, C., L’Hôte, V., Courbeyrette, R., Kratassiouk, G., Pinna, G., Cintrat, J., Wilkes, C. D., Derbois, C., Olaso, R., Deleuze, J., et al. (2019) · Journal of Cell Science · doi:10.1242/jcs.230748 · Cited by 27
“ERK1/2 activates EGR1 transcription by phosphorylating the ELK1 subunit of the SRF transcription factor (Bahrami and Drabløs, 2016).”
MethodBisagno, V., & Cadet, J. L. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.12.004 · Cited by 26
Seong, J., Oyong, G., & Cabrera, E. (2018) · doi:10.4103/2221-1691.227999 · Cited by 24
“On the other hand, Shyu et al. assumed that upregulation of c-fos and c-jun transcripts and following apoptosis may be due to the subsequent AP-1 formation and its involvement in mitogen-activated protein kinase pathway or sensitization of the cancer cells to the tumor necrosis factor-related apoptosis-inducing ligand…”
BackgroundInfluentialLay, B. P. P., Westbrook, R. F., Glanzman, D. L., & Holmes, N. M. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2966-17.2018 · Cited by 45
“In rodent models, early phases of protein synthesis have been identified with activation of immediate early genes, such as Arc, and through this activation, polymerization of the major cytoskeletal protein, actin (Steward et al., 2014; Bahrami and Drabløs, 2016).”
Ceylan, H. (2021) · Gene Reports · doi:10.1016/j.genrep.2021.101246 · Cited by 26
“Immediate early genes (IEGs) are rapidly and transiently activated genes in response to diverse molecular and cellular events (Bahrami and Drabl ø s, 2016).”
de Almeida, P. D. O., Barbosa, G. D. S., Ferreira, C. C. D. S., Bernardes, L. R., Dias, R. B., Sales, C. B. S., Valverde, L. D. F., Rocha, C. A. G., Soares, M. B. P., Bezerra, D. P., et al. (2021) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2021.109444 · Cited by 32
“FOS gene is related to immediate response and quickly expressed [28], while MAX gene is capable of forming homodimers and heterodimers with family members, which include MAD, MXL1, and MYC, these transcriptionally active dimer can promote cell proliferation as well as apoptosis [29].”
Background
Metadata
- Authors
- Bahrami, S., & Drabløs, F.
- Affiliations
- Norwegian University of Science and Technology (NO)
- Corresponding author
- Drabløs, Finn
- Venue
- Advances in Biological Regulation
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 62
- Pages
- 37-49
- ISSN
- 2212-4926 (ISSN-L)
- OpenAlex
- W2349918789
- Cited by
- 465
- References
- 109
- Citations by year
- 2026: 49 · 2025: 50 · 2024: 40 · 2023: 50 · 2022: 65 · 2021: 64 · 2020: 42 · 2019: 44 · 2018: 36 · 2017: 20 · 2016: 5
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Advances in Biological Regulation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Helse Midt-Norge
- Norges Teknisk-Naturvitenskapelige Universitet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- immediate early genes, gene expression regulation, transcription factor activation, MAPK signaling, ERK, signal transduction, enhancers, promoter regulation, stress response, immune response, cell differentiation, cancer
- MeSH terms
- Actins, Animals, Cell Differentiation, Cell Nucleus, Eukaryotic Cells, Gene Expression Regulation, Humans, Phosphorylation, Promoter Regions, Genetic, Transcription Factors, Signal Transduction, Genes, Immediate-Early, rhoA GTP-Binding Protein, Mitogen-Activated Protein Kinases, Extracellular Signal-Regulated MAP Kinases
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