Date of Award

5-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

College/School

College of Science and Mathematics

Department/Program

Biology

Thesis Sponsor/Dissertation Chair/Project Chair

Carlos A Molina

Committee Member

Alexis Khursigara

Committee Member

Kirsten Monsen-Collar

Abstract

Melanoma is a highly aggressive form of skin cancer frequently driven by mutations in the BRAF gene, particularly the BRAFⱽ⁶⁰⁰ᴱ variant, which leads to sustained activation of the MAPK signaling cascade. Recent studies implicate the cyclic AMP (cAMP) signaling axis in melanoma progression and therapeutic resistance, highlighting the role of the Inducible cAMP Early Repressor (ICER), a transcriptional antagonist of CREB and CREM. ICER is downregulated during melanomagenesis and subject to post-translational regulation via phosphorylation and ubiquitin-mediated degradation. To investigate ICER’s functional relevance in vivo, e utilized a zebrafish melanoma model harboring brafⱽ⁶⁰⁰ᴱ, tp53−/−, and mitf−/−mutations, in which mitf expression was restored through Tol2-mediated integration of a miniCoopR plasmid. Transgenic lines expressing either wild-type ICER (wtICER), a phosphorylation-deficient, ubiquitin-resistant ICER mutant (S35-41A-ICER), or an EGFP control were generated and monitored for survival and tumor progression. Western blot analysis confirmed that ICER expression is markedly reduced in tumor tissues relative to normal skin of zebrafish, supporting its role as a tumor suppressor. However, survival analysis revealed that wtICER expression paradoxically decreased overall survival and was associated with increased tumor invasiveness. In contrast, the S35-41A-ICER mutant significantly extended survival and reduced tumor malignancy. Histological examination further demonstrated that tumors in the wtICER cohort invaded deep into the musculature, while S35-41A-ICER fish displayed only benign hyperplasia. These findings suggest that ICER’s tumor-suppressive function depends on its post-translational stability and nuclear retention.

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