An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation
Abstract
The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1- and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.
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miR-21 expression was induced by AP-1 in response to Ras activation, and miR-21 mediated Ras-dependent downregulation of Pdcd4.
“miR-21 expression was induced by AP-1 in response to Ras activation, and miR-21 mediated Ras-dependent downregulation of Pdcd4 (Talotta et al., 2009)”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Talotta et al., 2009
An autoregulatory loop connecting miR-21 and Ras activation through AP-1 was illustrated in a rat thyroid cell system.
“Previously, an autoregulatory loop connecting miR-21 and Ras activation through AP-1 was illustrated in a rat thyroid cell system (Talotta et al., 2009).”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Talotta et al., 2009
Cites
AP-1 as a regulator of cell life and death
Shaulian, E., & Karin, M. (2002) · Nature Cell Biology · doi:10.1038/ncb0502-e131 · Cited by 2,961 · cited 2× · see citing works
“…proliferation, apoptosis, tumor invasiveness and angiogenesis, the transcription factor AP-1, mainly formed by dimerization between members of the JUN and FOS protein families, is implicated in multiple hallmarks of cancer (Shaulian and Karin, 2002; Eferl and Wagner, 2003; Ozanne et al., 2007).”
BackgroundMeng, F., Henson, R., Lang, M., Wehbe, H., Maheshwari, S., Mendell, J. T., Jiang, J., Schmittgen, T. D., & Patel, T. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.02.057 · Cited by 984 · see citing works
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Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21
Hatley, M. E., Patrick, D. M., Garcia, M. R., Richardson, J. A., Bassel-Duby, R., van Rooij, E., & Olson, E. N. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.08.013 · Cited by 626 · see citing works
“miR-21 expression was induced by AP-1 in response to Ras activation, and miR-21 mediated Ras-dependent downregulation of Pdcd4 (Talotta et al., 2009), a known negative regulator of AP-1 transactivation (Goke et al.”
InfluentialDownregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo
Gaur, A. B., Holbeck, S. L., Colburn, N. H., & Israel, M. A. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor033 · Cited by 180 · see citing works
Upregulation of miR-21 in Cisplatin Resistant Ovarian Cancer via JNK-1/c-Jun Pathway
Echevarría-Vargas, I. M., Valiyeva, F., & Vivas-Mejía, P. E. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097094 · Cited by 118 · see citing works
Ferraro, A., Kontos, C. K., Boni, T., Bantounas, I., Siakouli, D., Kosmidou, V., Vlassi, M., Spyridakis, Y., Tsipras, I., Zografos, G., et al. (2014) · Epigenetics · doi:10.4161/epi.26842 · Cited by 111 · see citing works
- Authors
- Talotta, F., Cimmino, A., Matarazzo, M. R., Casalino, L., De Vita, G., D'Esposito, M., Di Lauro, R., & Verde, P.
- Affiliations
- Institute of Genetics and Biophysics (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Corresponding author
- Verde, P
- Venue
- Oncogene
- Published
- 2008-10-13
- Volume
- 28
- Issue
- 1
- Pages
- 73-84
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1980718338
- Cited by
- 242
- References
- 6
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 10 · 2019: 6 · 2018: 10 · 2017: 13 · 2016: 15 · 2015: 21 · 2014: 16 · 2013: 27 · 2012: 19
- FWCI
- 8.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- miR-21, PDCD4, AP-1, Ras transformation, autoregulatory loop, microRNA, oncogenic microRNA, PTEN, transcriptional regulation, carcinogenesis, post-transcriptional regulation
- MeSH terms
- Fos-Related Antigen 1, Animals, Cell Survival, Cell Transformation, Neoplastic, Homeostasis, Humans, Thyroid Gland, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-fos, ras Proteins, Transcription Factor AP-1, MicroRNAs, Cell Line, Tumor, Apoptosis Regulatory Proteins, PTEN Phosphohydrolase, Rats
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