PUBLICATION
Phosphorylation Deficient Inducible cAMP Early Repressor (ICER) Modulates Tumorigenesis and Survival in a Transgenic Zebrafish (Danio rerio) Model of Melanoma
- Authors
- Wheelan, J., Spigelman, M., Cirinelli, A., Reilly, J., Molina, C.A.
- ID
- ZDB-PUB-250729-8
- Date
- 2025
- Source
- Biology Open : (Journal)
- Registered Authors
- Keywords
- CREB, CREM, Cancer, ICER, Melanoma, PKA
- MeSH Terms
-
- Zebrafish/genetics
- Carcinogenesis*/genetics
- Signal Transduction
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Proto-Oncogene Proteins B-raf/genetics
- Animals
- Mutation
- Phosphorylation
- Disease Models, Animal
- Animals, Genetically Modified
- Melanoma*/genetics
- Melanoma*/metabolism
- Melanoma*/mortality
- Melanoma*/pathology
- Cyclic AMP Response Element Modulator*/genetics
- Cyclic AMP Response Element Modulator*/metabolism
- Gene Expression Regulation, Neoplastic
- PubMed
- 40719625 Full text @ Biol. Open
Citation
Wheelan, J., Spigelman, M., Cirinelli, A., Reilly, J., Molina, C.A. (2025) Phosphorylation Deficient Inducible cAMP Early Repressor (ICER) Modulates Tumorigenesis and Survival in a Transgenic Zebrafish (Danio rerio) Model of Melanoma. Biology Open. :.
Abstract
Melanoma, the most lethal form of skin cancer, is commonly associated by mutations in the BRAF gene, particularly BRAFV600E, which drives tumor proliferation via ERK1/2 signaling cascade. While BRAF inhibitors initially demonstrate efficacy, therapeutic resistance remains a significant challenge. Emerging evidence implicates the cAMP signaling pathway, particularly the cAMP response element-binding protein (CREB) and its repressor, Inducible cAMP Early Repressor (ICER), in melanoma progression and drug resistance. ICER, a transcriptional repressor regulated via Ras/MAPK-mediated phosphorylation and ubiquitination, is degraded in melanoma, undermining its tumor-suppressive role. In a brafV600E; p53(loss of function) transgenic zebrafish (Danio rerio) model, we investigated the role of a ubiquitin-resistant ICER mutant (S35-41A-ICER) in tumor progression. Transgenic fish expressing S35-41A-ICER exhibited extended survival and reduced tumor invasiveness compared to wild-type ICER. RNA sequencing revealed dysregulation of CREB/CREM targets and compensatory pathways, including Rap1 and PI3K/AKT signaling, as well as candidate gene targets of ICER regulation, including the Protein Kinase A catalytic subunit prkacaa. Our findings suggest that a ubiquitin resistant ICER mitigates melanoma progression and represses oncogenic pathways in a brafV600E melanoma context.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping