Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation
Abstract
Ras is one of the most frequently activated oncogenes in cancer. Two mitogen-activated protein kinases (MAPKs) are important for ras transformation: extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase 2 (JNK2). Here we present a downstream signal amplification cascade that is critical for ras transformation in murine embryonic fibroblasts. This cascade is coordinated by ERK and JNK2 MAPKs, whose Ras-mediated activation leads to the enhanced levels of three oncogenic transcription factors, namely, c-Myc, activating transcription factor 2 (ATF2) and ATF3, all of which are essential for ras transformation. Previous studies show that ERK-mediated serine 62 phosphorylation protects c-Myc from proteasomal degradation. ERK is, however, not alone sufficient to stabilize c-Myc but requires the cooperation of cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncogene that counteracts protein phosphatase 2A-mediated dephosphorylation of c-Myc. Here we show that JNK2 regulates Cip2a transcription via ATF2. ATF2 and c-Myc cooperate to activate the transcription of ATF3. Remarkably, not only ectopic JNK2, but also ectopic ATF2, CIP2A, c-Myc and ATF3 are sufficient to rescue the defective ras transformation of JNK2-deficient cells. Thus, these data identify the key signal converging point of JNK2 and ERK pathways and underline the central role of CIP2A in ras transformation.
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CIP2A impacts oncogenic RAS signaling and MYC activity in vivo.
“Impact of CIP2A on both oncogenic RAS signaling [10,13,36] and MYC activity in vivo [10,12,22]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [36]
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Zhao, Y., Li, Y., Han, J., Liu, T., Guan, Q., Zhao, P., Guo, L., Liu, K., & He, D. (2014) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2014.1615 · Cited by 13 · see citing works
Oncoprotein CIP2A promotes the disassembly of primary cilia and inhibits glycolytic metabolism
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ATF3-Induced Mammary Tumors Exhibit Molecular Features of Human Basal-Like Breast Cancer
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Krüppel‐like factor 6 interferes with cellular transformation induced by the H‐ ras oncogene
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p90/CIP2A mediates breast cancer cell proliferation and apoptosis
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Assessment of the Potential of Pathological Stains in Human Prostate Cancer
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Self-citationCip2a induces arginine biosynthesis and promotes tumor progression in non‐small cell lung cancer
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IDENTIFICATION AND CHARACTERIZATION OF CIP2A AS A NOVEL ONCOGENIC INHIBITOR OF PP2A
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- Authors
- Mathiasen, D. P., Egebjerg, C., Andersen, S. H., Rafn, B., Puustinen, P., Khanna, A., Daugaard, M., Valo, E., Tuomela, S., Bøttzauw, T., Nielsen, C. F., Willumsen, B. M., Hautaniemi, S., Lahesmaa, R., Westermarck, J., Jäättelä, M., & Kallunki, T.
- Affiliations
- Danish Cancer Society (DK)
- University of Tampere (FI)
- University of Helsinki (FI)
- Åbo Akademi University (FI)
- University of Copenhagen (DK)
- Corresponding author
- Kallunki, T
- ORCID
- Venue
- Oncogene
- Published
- 2011-06-27
- Volume
- 31
- Issue
- 3
- Pages
- 390-401
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2067854511
- Cited by
- 44
- References
- 65
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 8 · 2013: 9 · 2012: 4
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- ERK, Ras transformation, c-Myc, ATF2, ATF3, CIP2A, protein phosphatase 2A, proteasomal degradation, MAPK signaling, transcriptional regulation, murine embryonic fibroblasts
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Cells, Cultured, Fibroblasts, Mice, Inbred BALB C, Mice, Nude, Genes, ras, Proto-Oncogene Proteins c-myc, ras Proteins, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 9, Mice, Activating Transcription Factor 2, Activating Transcription Factor 3, Protein Phosphatase 2
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