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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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“suggesting that acute social defeat stress induces a transient but robust inflammatory response that contributes to short-term behavioral and physiological changes”
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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“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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CRISPRi with barcoded expression reporters dissects regulatory networks in human cellsPreprint
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“IEGs are efficient markers of neural activity as they are transcribed transiently and rapidly in response to specific stimulations inducing neural activity without de novo protein synthesis (Clayton, 2000; Minatohara et al., 2015; Bahrami and Drabløs, 2016).”
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“Their expression is regulated by several signalling pathways, including the RHOA/ROCK, ERK MAPK, P38 MAPK, or PI3K pathways [82].”
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A Csde1-Strap complex regulates plasma cell differentiation by coupling mRNA translation and decay
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Clorfl86/RHEX Is a Negative Regulator of SCF/KIT Signaling in Human Skin Mast Cells
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“Nonetheless, since RHEX countered the activation of ERK in SCF-stimulated MCs, it accordingly limited the induction of IEGs, genes rapidly induced following stimulation without the necessity of new protein synthesis [97,98].”
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“In general, the products of IEGs play a major role in the activation of downstream signaling pathways essential for stimulating an immune response [11].”
BackgroundInfluentialOxycodone preemptive analgesia after endoscopic plasma total adenotonsillectomy in children
Wu, J., Gui, Q., Wang, J., Ye, J., Xia, Z., Wang, S.-F., Liu, F., Kong, F., & Zhong, L. (2020) · Medicine · doi:10.1097/md.0000000000019004 · Cited by 7
“Since intravenous analgesia aims to decrease pain and to alleviate negative experiences like nausea, vomiting, and restlessness, c-fos mRNA levels should be decreased by successful analgesia.([25]) In the present study, the relative transcription levels of the c-fos mRNA in serum were increased along with the severity…”
BackgroundResultVitorino, F. N. D. L., Montoni, F., Moreno, J. N., de Souza, B. F., Lopes, M. D. C., Cordeiro, B., Fonseca, C. S., Gilmore, J., Sardiu, M., Reis, M. S., et al. (2018) · Proteomics · doi:10.1002/pmic.201800203 · Cited by 7
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“The total time (including the test = 60min) is when immediate early gene expression peaks and coincides with peak transcriptional expression associated with drug-seeking behaviors as previously observed 50,76,80 – 83 .”
Mechanisms of biased agonism by Gα i/o -biased stapled peptide agonists of the relaxin-3 receptor
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“Moreover, SRE reporter gene activation is preceded by the activation of ETS like-1 protein (Elk-1) and ERK1/2 ( 65 ).”
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“This analysis was performed as previously described 16 and is summarised in the Supporting Information files.”
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“C-fos was the first transcription factor in the immediate early gene family that was found to be dependent on neuronal activity and to respond quickly to a series of stimuli received by neurons (Morgan and Curran, 1988; Sagar et al., 1988; Hughes and Dragunow, 1995; Bahrami and Drablos, 2016).”
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“Both Egr-1 and c-Fos are transcription factors which can be activated by a plethora of stimuli and induce a secondary response (Bahrami and Drabløs 2016).”
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“A unique group of genes, which are quickly transcribed in response to extracellular stimuli without de novo protein synthesis and thereby capable of causing rapid, adaptive changes in cellular function, are known as immediate early genes (IEGs) [1].”
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SLFN11, far from being limited to responding to cancer DNA damage
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“And SLFN11, as a member of IEGs, can upregulate the expression of ERK and MAPK pathways, modulate innate immunity, and influence the efficacy of tumor therapy [78], [85], [132].”
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“It is clear that the IEGs represent a key component of these interactions and provide rapid and dynamic response to neuronal activity through the expression regulation of secondary genes [36,42].”
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“In addition, it is worth considering that IEGs show rapid pre-mRNA induction and RNA polymerase recruitment compared to secondary/delayed response genes (Bahrami and Drablos, 2016).”
BackgroundThe hardwired transcriptional response to DNA damage
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“Mock WT Δ prgJ Mock WT Δ prgJ Mock WT Δ prgJ Both Egr1 and Nr4a1 are known immediate early genes that are rapidly transcribed in many cell types within minutes in response to a range of cellular stresses 51 – 53 .”
Tenhaken, V., Seternes, O. M., Cascorbi, I., & Bruckmueller, H. (2025) · BMC Cancer · doi:10.1186/s12885-025-14434-z · Cited by 3
“DUSP2 is one of these essential negative regulators of the MAPK pathway which ensures a tight and efficient control of MAPKs under physiological conditions, and these genes are strictly regulated themselves e.g. by RNA-binding proteins or microRNAs [44].”
Enhancing titers of therapeutic lentiviral vectors using PKC agonists
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“60 ,61,62 Our data suggested a protective role of AP-1 since this transcriptional signature could be found in both, affected YAP pKO and healthy TAZ pKO mice.”
CREB Is Critically Implicated in Skin Mast Cell Degranulation Elicited via FcεRI and MRGPRX2
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“Both Egr1 and Nr4a1 are known immediate early genes that are rapidly transcribed in many cell types within minutes in response to a range of cellular stresses 48–50 .”
BackgroundWen, X., Pu, L., Zhang, W., Tengfei, M., & Guang-shun, W. (2024) · Thoracic Cancer · doi:10.1111/1759-7714.15301 · Cited by 4
“25 IER2 regulates hepatocellular carcinoma migration and invasion via focal adhesion kinase (FAK) and plays an important role in regulating endothelial cell motility, cell matrix adhesion and angiogenesis in vitro.”
BackgroundGPR55 inhibits the pro-adipogenic activity of anandamide in human adipose stromal cells
Ruhl, T., Nuptybayeva, A., Kim, B., & Beier, J. P. (2023) · Experimental Cell Research · doi:10.1016/j.yexcr.2023.113908 · Cited by 5
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“FOS is an AP- 1 transcription factor subunit (Bahrami & Drabløs, 2016), and lack of Fos expression in vitro and in vivo led to increased IL6 and TNFα production following LPS treatment (Ray et al., 2006).”
BackgroundWu, H. Q., Suo, G., Li, T., Zheng, Y., Li, H., Shen, F., Wang, Y., Ni, H., & Wu, Y. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01270-4 · Cited by 6
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Chemotherapy suppresses SHH gene expression via a specific enhancer.
Zhang, Y.-F., Lin, J.-Q., Yang, K.-B., & Yue, Z.-C. (2022) · Journal of genetics and genomics = Yi chuan xue bao · doi:10.1016/j.jgg.2022.08.002 · Cited by 4
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“tion of 31 genes, including immediate early gene response genes (39) such as IER2 and IER3, FIG 5 ACD is sufficient, but not necessary, for dissemination.”
Backgroundα-glucosyl-rutin activates immediate early genes in human induced pluripotent stem cells.
Miyake, T., Kuge, M., Matsumoto, Y., & Shimada, M. (2021) · Stem Cell Research · doi:10.1016/j.scr.2021.102511 · Cited by 4
CDK8 and CDK19 kinases have non-redundant oncogenic functions in hepatocellular carcinomaPreprint
Bacevic, K., Prieto, S., Caruso, S., Camasses, A., Dubra, G., Ursic-Bedoya, J., Lozano, A., Butterworth, J. A., Zucman-Rossi, J., Hibner, U., et al. (2019) · bioRxiv · doi:10.1101/789586 · Cited by 4
Narodova, E. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052511 · Cited by 3
Sequential RNA polymerase II activation drives human hematopoiesis
Janssens, D. H., Codomo, C. A., Otto, D. J., Silberstein, L., Ahmad, K., & Henikoff, S. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116802 · Cited by 3
“Prior to immune activation, Pol II is paused at promoter-proximal regions of immune response genes and the large subunit of Pol II is phosphorylated on Serine 5 of the heptapeptide repeats in the C-terminal domain (CTD) 3 .”
Emerging roles of Midnolin in Cancer, Parkinson’s Disease, and Metabolic dysfunction
Kalyan, M., Singh, P. K., & Verma, A. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-11120-y · Cited by 3
“This is brought about broadly by a two-step process, that is, firstly, there is activation of early response brought about by genes known as Immediate early genes (IEGs), followed by a secondary activation of late response genes which respond to the initial stimulus [2 , 11].”
Menon, R., Kimmel, P., Otto, E., Subramanian, L., Berthier, C., O'Connor, C., Godfrey, B., Naik, A., Sarwal, M., Woodle, E. S., et al. (2025) · medRxiv · doi:10.1101/2025.03.17.25324134 · Cited by 3
“Early stress response genes can be activated within minutes after stimulation 16, 17 .”
Distinct molecular mechanisms of stress habituation in the mouse hippocampusPreprint
Waag, R., von Ziegler, L., Sturman, O., Sonder, E., Leonardi, J., Frei, S., Gapp, K., Germain, P., & Bohacek, J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.04.641433 · Cited by 3
“We observe that the members of cluster 1 are strongly enriched for CREB1 and SRF transcription factor activity, both crucial for IEG induction (Bahrami and Drabløs, 2016).”
Batta, S., Rio, M., Lebot, C., Baron-Menguy, C., Bodet, M., Moutaoukil, R., Ruz, R. L., Babahnini, I., Loirand, G., & Vion, A.-C. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115288 · Cited by 3
Guan, X., Xu, L., Liu, J., Fei, H., & Wang, C. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s503326 · Cited by 5
“12 Recent study has shown that midnolin is a key regulator of IEG protein degradation.”
Kawataki, S., Kubota, Y., Katayama, K., Imoto, S., & Takekawa, M. (2024) · Cancer Science · doi:10.1111/cas.16389 · Cited by 4
“19 As many IEGs encode TFs (e.g., EGR1 and c-Fos), their induction further promotes the expression of various genes that control cell proliferation, differentiation, and carcinogen - esis.”
Li, B.-N., Edick, A. M., Fox, M. K., Doelman, J., Burgos, S., & Cant, J. (2024) · bioRxiv · doi:10.1101/2024.06.01.596926 · Cited by 3
Gilbert, H. T. J., Wignall, F., Zeef, L., Hoyland, J., & Richardson, S. M. (2024) · JOR Spine · doi:10.1002/jsp2.1315 · Cited by 3
“…(cyclohexamide) to ascertain whether specific gene responses were reliant upon the translation of other genes, thereby enabling a distinction to be made between the primary responses which do not require de novo protein synthesis for transcription regulation 24 and secondary responses which do.”
BackgroundCytotoxic T lymphocytes require transcription for infiltration but not target cell lysis
Richard, A. C., Ma, C. Y., Marioni, J. C., & Griffiths, G. M. (2023) · EMBO Reports · doi:10.15252/embr.202357653 · Cited by 5
“…of pre-formed transcription factors, specifically NFAT, which rapidly moves to the nucleus following TCR-induced calcium flux, and ELK1, which is down-stream of the MEK/ERK pathways (Goldfeld et al , 1993; Shao et al , 1997; Falvo et al , 2010; Bahrami & Drablos, 2016; Trebak & Kinet, 2019).”
BackgroundTranscriptomic Analysis Reveals Novel Regulators of the Scots Pine Stilbene Pathway
Paasela, T., Lim, K.-J., Pavicic, M., Harju, A., Venäläinen, M., Paulin, L., Auvinen, P., Kärkkäinen, K., & Teeri, T. (2023) · Plant and Cell Physiology · doi:10.1093/pcp/pcad089 · Cited by 3
“Protein synthesis inhibitors, like CHX, are used for identifying whether the initiation of gene expression requires de novo protein synthesis or is regulated by preexisting TFs (Tullai et al. 2007, Bahrami and Drabløs 2016).”
BackgroundMethodBahl, E., Chatterjee, S., Mukherjee, U., Elsadany, M., Vanrobaeys, Y., Lin, L.-C., McDonough, M. C., Resch, J., Giese, K., Abel, T., et al. (2023) · bioRxiv · doi:10.1101/2022.04.08.487573 · Cited by 3
Summers, J. A., & Jones, K. L. (2023) · bioRxiv · doi:10.1101/2023.05.30.542876 · Cited by 3
“Clusters 0, 2, 4, 9, and 14 were determined to be different populations of endothelial cells, based on expression of several endothelial cell (EC) markers (CDH5, PECAM1 and VWF).”
Hashoul, D., Saliba, W., Broza, Y., & Haick, H. (2023) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10519 · Cited by 3
“32,33 For example, EGR1, DUSP1, and FOS show a rapid increase followed by a stronger upregulation of JUN after exposure to house dust mite in airway epithelial cells.”
BackgroundHussainy, M., Korsching, S., & Tresch, A. (2022) · bioRxiv · doi:10.1038/s41598-022-20106-w · Cited by 3
Atlas of regulated target genes of transcription factors (ART-TF) in human ES cells
Sharov, A. A., Nakatake, Y., & Wang, W. (2022) · BMC Bioinformatics · doi:10.1186/s12859-022-04924-3 · Cited by 2
“Regulation via promoter is apparently faster, and thus, it is involved in such functions as cell-cycle and immune response that require immediate activation or repression [41].”
BackgroundVerma, N., Alyethodi, R. R., Kathuria, A., Alex, R., Hussain, S., Singh, U., Tyagi, S., SIROHI, A. S., Kumar, S., Sengar, G. S., et al. (2021) · International Journal of Biometeorology · doi:10.1007/s00484-021-02084-2 · Cited by 3
“Similar to c-FOS and JUN in the present study, a lack of methylation in HSP 60 ubiquitin promoter regions was reported and suggestive of a methylation-free state of CpG island (CGI), which is causally related to their function as promoters (Vinoth et al. 2018). c-FOS and JUN genes are early response genes; i.e., they…”
BackgroundInfluentialPorter, W., Snowden, E., Hahn, F., Ferguson, M., Tong, F., Dillmore, W. S., & Blaesius, R. (2020) · PLoS ONE · doi:10.1371/journal.pone.0238594 · Cited by 3
Vadakkan, K. (2018) · doi:10.7287/peerj.preprints.27343v1 · Cited by 3
“Even though mRNA for IEGs may appear in cells within minutes after stimulation (Bahrami and Drabløs, 2016), it”
BackgroundInfluentialPeripheral mechanisms of the stress-protective effect of iodine-containing thyroid hormones
Gorodetskaya, I., Gusakova, E., & Evdokimova, O. (2016) · Vestnik of Vitebsk State Medical University · doi:10.22263/2312-4156.2016.6.41 · Cited by 3
Bordbar, A., Bloem, B., Lloyd, C., Johnston, T., Schneider, J. S., Bézard, E., Pioli, E. Y., Li, Q., Tawfeeq, C., Pham, N. V., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.aec7409 · Cited by 2
Transcriptional predictors of rescue behaviour in ants
Jaimes-Nino, L. M., Bar, A., Scharf, I., & Foitzik, S. (2026) · Journal of Experimental Biology · doi:10.1242/jeb.252086 · Cited by 2
“Likewise, they are unlikely to reflect differences in time spent in the arena, given that transcriptional responses generally require 20 min to several hours to manifest (Bahrami and Drabløs, 2016; O ’ Brien and Lis, 1993; Walton et al., 1999).”
Serum withdrawal establishes a stress-dominant entry state during myogenic differentiation
Lyu, Z., Shao, C., Yang, R., Yu, Q., Yang, M., Yang, G., & Wang, Z. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1823860 · Cited by 2
“Practically, early marker shifts can therefore admit multiple, non-exclusive interpretations (Herschman, 1991; Bahrami and Drabløs, 2016): immediate-early and integrated-stress responses may be captured alongside transcriptional changes more tightly linked to commitment, with stronger coupling to…”
InfluentialProgrammable, target-induced fluorogenic CRISPR–tDeg platform for live-cell RNA visualization
Zhong, H., Zhou, J., Qin, F., Zhang, X., & Chen, M. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag279 · Cited by 1
“To this end, we selected FOS and MYC, two representative endogenous RNAs that are not highly expressed under our experimental conditions and span a range of moderate to low expression levels [ 38 ].”
Jin, M., Schneikert, J., Wegner, A., Zuberbier, T., & Babina, M. (2026) · Cells · doi:10.3390/cells15050398 · Cited by 2
“IEGs are rapidly induced by various stimuli independently of new protein expression [62,63].”
Histone variant H2BE controls activity-dependent gene expression and homeostatic scaling
Feierman, E. R., Paranjapye, A., Sangree, A. K., Ahmad, R., Maroni, M. J., Qiu, Q., Choi, K., Fuccillo, M. V., Wu, H., & Korb, E. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116694 · Cited by 4
AP-1 mediated chromatin changes govern alveolar type 2 cell transition in lung injury-repair
Lynch, A. M., Noun, T., Yang, S., Zhou, T.-L., Evans, S. E., Kadara, H., & Chen, J.-C. (2025) · bioRxiv · doi:10.1101/2025.10.25.684549 · Cited by 2
“Second, T2’s defining feature of AP-1 activation—typically associated with immediate early responses 43 —along with its signature gene ontology terms for cell adhesion and migration (Fig.”
Shen, Y., Luo, B., Zhang, Q., Li, H., Hu, Y. C., & Chen, M. H. (2025) · Scientific Reports · doi:10.1038/s41598-025-95451-7 · Cited by 2
Brain-wide immunolabeling and tissue clearing applications for engram research
Franceschini, A., Jin, M., Chen, C. W., Silvestri, L., Mastrodonato, A., & Denny, C. A. (2025) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2025.108032 · Cited by 5
Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia
Chen, Z., Wu, F., Li, Y., Li, L., Lei, Y., Gao, S., Chen, T., Xie, Y., Xiao, J., Zeng, H., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20241248 · Cited by 3
Rothschadl, M. J., Sathyanesan, M., & Newton, S. S. (2023) · Life · doi:10.3390/life13091826 · Cited by 2
“IEG activation is thought to be regulated by multiple pathways including ERK, RhoA-actin, p38 MAPK, and PI3K [44–46].”
BackgroundNozari, A., Do, S., & Trudeau, V. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.727777 · Cited by 2
High-resolution single cell transcriptome analysis of zebrafish sensory hair cell regenerationPreprint
Baek, S., Tran, N. T., Díaz, D. C., Tsai, Y.-Y., Acedo, J. N., Lush, M. E., & Piotrowski, T. (2021) · bioRxiv · doi:10.1101/2021.07.15.452338 · Cited by 2
Dutta, M., Saha, A., Moin, M., & Kirti, P. (2021) · bioRxiv · doi:10.1101/2021.06.28.449579 · Cited by 2
Sun, G., Shvab, A., Leclerc, G. J., Li, B., Beckedorff, F., Shiekhattar, R., & Barredo, J. C. (2021) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0808 · Cited by 3
“IEGs expression is known to be altered transiently and rapidly in response to stimuli without the need of intermediate protein synthesis (13), and based on our data we postulate PKD mediates an adaptive survival mechanism in response to cellular stress induced by AICAR (and possibly other stimuli) in ALL cells.”
BackgroundControl of RNA polymerase II promoter-proximal pausing by DNA supercoilingPreprint
Herrero-Ruíz, A., Martínez-García, P. M., Terrón-Bautista, J., Lieberman, J., Jimeno-González, S., & Cortés-Ledesma, F. (2020) · bioRxiv · doi:10.1101/2020.05.12.091058 · Cited by 2
“In fact, there was a clear enrichment of IEGs (Figure S1B), genes that, as mentioned above, are highly regulated, and activated through protein synthesis-independent rapid bursts of transcription shortly after different types of stimuli (Bahrami and Drablos, 2016).”
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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