ArticleMolecular and cellular biology2007
Ubiquitin-independent proteasomal degradation of Fra-1 is antagonized by Erk1/2 pathway-mediated phosphorylation of a unique C-terminal destabilizer.
Article in Molecular and cellular biology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 119 citations in OpenAlex.
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- Oncogenic KRAS/ERK/JUNB signaling suppresses differentiation regulator GATA6 in pancreatic cancer.The Journal of clinical investigation · 2026Article
- Dual FAK and EPHA2 targeting by brigatinib tackles PARP inhibitor adaptive survival response in high-grade serous ovarian cancer.Science translational medicine · 2026Article
- Comprehensive map of the regulatory network triggered by MET exon 14 skipping reveals important involvement of the RAS-ERK signaling pathway.Cell death & disease · 2025Article
- Degrons: defining the rules of protein degradation.Nature reviews. Molecular cell biology · 2025Review
- Article
- The Activation of the CCND1 Promoter by AP-1 and SOX Transcription Factors in PC3 Prostate Cancer Cells Can Be Prevented by Anacardic Acid Analogs.Cell biochemistry and biophysics · 2025Article
- Endothelial FOSL1 drives angiotensin II-induced myocardial injury via AT1R-upregulated MYH9.Acta pharmacologica Sinica · 2025Article
- FRA1 controls acinar cell plasticity during murine KrasDevelopmental cell · 2024Article
- CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation.The Biochemical journal · 2024Article
- Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.Science (New York, N.Y.) · 2024Article
- FOSL1's Oncogene Roles in Glioma/Glioma Stem Cells and Tumorigenesis: A Comprehensive Review.International journal of molecular sciences · 2024Review
- PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis.Cancer research · 2024Article
- PARP7-mediated ADP-ribosylation of FRA1 promotes cancer cell growth by repressing IRF1- and IRF3-dependent apoptosis.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Overexpression of FRA1 (Cells · 2023Article
- Multiple Fra-1-bound enhancers showing different molecular and functional features can cooperate to repress gene transcription.Cell & bioscience · 2023Article
- FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer.International journal of molecular sciences · 2023Review
- Recurrent FOSL1 rearrangements in desmoplastic fibroblastoma.The Journal of pathology · 2023Article
- Emerging Role of Plant-Based Dietary Components in Post-Translational Modifications Associated with Colorectal Cancer.Life (Basel, Switzerland) · 2023Review
11 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fra-1, a transcription factor that is phylogenetically and functionally related to the proto-oncoprotein c-Fos, controls many essential cell functions. It is expressed in many cell types, albeit with differing kinetics and abundances. In cells reentering the cell cycle, Fra-1 expression is transiently stimulated albeit later than that of c-Fos and for a longer time. Moreover, Fra-1 overexpression is found in cancer cells displaying high Erk1/2 activity and has been linked to tumorigenesis. One crucial point of regulation of Fra-1 levels is controlled protein degradation, the mechanism of which remains poorly characterized. Here, we have combined genetic, pharmacological, and signaling studies to investigate this process in nontransformed cells and to elucidate how it is altered in cancer cells. We report that the intrinsic instability of Fra-1 depends on a single destabilizer contained within the C-terminal 30 to 40 amino acids. Two serines therein, S252 and S265, are phosphorylated by kinases of the Erk1/2 pathway, which compromises protein destruction upon both normal physiological induction and tumorigenic constitutive activation of this cascade. Our data also indicate that Fra-1, like c-Fos, belongs to a small group of proteins that may, under certain circumstances, undergo ubiquitin-independent degradation by the proteasome. Our work reveals both similitudes and differences between Fra-1 and c-Fos degradation mechanisms. In particular, the presence of a single destabilizer within Fra-1, instead of two that are differentially regulated in c-Fos, explains the much faster turnover of the latter when cells traverse the G(0)/G(1)-to-S-phase transition. Finally, our study offers further insights into the signaling-regulated expression of the other Fos family proteins.
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