Date of Award

8-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School

College of Science and Mathematics

Department/Program

Earth and Environmental Studies

Thesis Sponsor/Dissertation Chair/Project Chair

Carlos A. Molina

Committee Member

Charles Du

Committee Member

Robert Meredith

Committee Member

Pranela Rameshwar

Abstract

Melanoma is the deadliest form of skin cancer, with 100,640 new cases and 8,290 deaths estimated in the United States in 2024. While targeted therapies and immunotherapy have improved patient outcomes, resistance remains a major challenge, necessitating new therapeutic approaches. Approximately 50% of melanomas harbor BRAFⱽ⁶⁰⁰ᴱ mutations, leading to constitutive MAPK pathway activation. Targeted small molecule therapies such as BRAF and MEK inhibitors are available and initially reduce tumor burden, however resistance frequently occurs, likely through many pathways including compensatory activation of cAMP signaling. ICER (Inducible cAMP Early Repressor), a transcriptional repressor of CREB-mediated gene expression, is absent in melanoma but strongly upregulated in regression, suggesting a tumor-suppressive role. ICER is post-translationally regulated via phosphorylation and ubiquitination, leading to its proteasomal degradation in melanoma cells. This study aims to identify ICER-interacting proteins, including ubiquitin ligases involved in its degradation, using co-immunoprecipitation and mass spectrometry. Additionally, this research investigated the role of ICER phosphorylation in melanoma progression using a transgenic zebrafish model expressing brafV600E, p53 loss-of-function, and mitf loss-of-function. By analyzing survival, histology, and transcriptomic changes in wild-type and phosphorylation-resistant ICER mutants, this study describes ICER’s role in melanoma progression and potential downstream targets, which can inform future therapeutic applications.

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