Is ICER, a protein with anti tumor functions, paradoxically eliciting refractory tumors?
Presentation Type
Poster
Faculty Advisor
Carlos Molina
Access Type
Open Access
Start Date
26-4-2023 9:45 AM
End Date
26-4-2023 10:44 AM
Description
Skin cancer is the most common cancer in the United States. Melanoma, which forms in melanocytes or pigment-producing cells, is the most lethal type of skin cancer. The number of new cases of melanoma has been increasing for at least 40 years. Although chemotherapy, radiation therapy, immunotherapy, targeted therapy, and surgery can be effective cancer treatments, unresponsiveness to treatments has been increasing throughout the past decade. More specifically, this is due to patients’ cancer cells building resistance to therapy. Inducible cAMP Early Repressor (ICER) is a transcription factor that is found in all eukaryotes. Deregulation of ICER protein is a common phenomenon in many cancers, including melanomas. ICER possesses tumor-suppressing abilities, and its overexpression of ICER blocks cells in mitosis, eliciting cell death and therefore, halting the tumorigenicity of cancer cells. Paradoxically, ICER elicits aggressive tumors in a zebrafish model for melanoma. Common therapies like targeted therapy include inhibitors of the Mitogen-Activate Protein Kinase (MAPK) pathway. The cAMP pathway, and the transcription factors involved in this pathway in human melanoma, have been highlighted in resistance to RAF/MEK inhibitors. ICER, as a repressor of gene expression (an antagonist of CREB) of the cAMP pathway, might be involved in this observed resistance. In order to test this hypothesis we developed transgenic zebrafish lines expressing two different forms of ICER in the zebrafish model for melanoma, Tg(mitfa:BRAFV600E); mitfa(lf); p53(lf). The two different forms of zebrafish ICER-Iɣ were: wild-type- (wt-) and S35&41A-ICER. In S35&41A-ICER, serines 35 and 41 were substituted for alanines in order to prevent phosphorylation. We have shown before that phosphorylation on serines 41 by ERK1 was a prerequisite for polyubiquitination and proteasomal degradation, whereas phosphorylation on serine 35 by the mitotic kinase cdk1 was necessary for monoubiquitination and alter subcellular localization to the cytosol. Fish survival curves showed that ICER (wt-) form significantly accelerated melanoma onset compared to EGFP control. wt-ICER succumbed to malignancies much faster than control EGFP and S35&41A-ICER expressing fish. In contrast, the zebrafish expressing S35&41A phosphorylation mutant ICER have a significantly longer life than EGFP control. Melanocytes expressing wt- ICER grew in confluent patches in zebrafish, unlike melanocytes in the EGFP- control and S35&41A-ICER expressing zebrafish, which grew in a wild-type stripe pattern. A pathological and molecular analysis will be presented during the poster session investigating the hypothesis that this presumed paradox is related to the development of a refractory melanoma of the ICER-expressing melanocytes.
Is ICER, a protein with anti tumor functions, paradoxically eliciting refractory tumors?
Skin cancer is the most common cancer in the United States. Melanoma, which forms in melanocytes or pigment-producing cells, is the most lethal type of skin cancer. The number of new cases of melanoma has been increasing for at least 40 years. Although chemotherapy, radiation therapy, immunotherapy, targeted therapy, and surgery can be effective cancer treatments, unresponsiveness to treatments has been increasing throughout the past decade. More specifically, this is due to patients’ cancer cells building resistance to therapy. Inducible cAMP Early Repressor (ICER) is a transcription factor that is found in all eukaryotes. Deregulation of ICER protein is a common phenomenon in many cancers, including melanomas. ICER possesses tumor-suppressing abilities, and its overexpression of ICER blocks cells in mitosis, eliciting cell death and therefore, halting the tumorigenicity of cancer cells. Paradoxically, ICER elicits aggressive tumors in a zebrafish model for melanoma. Common therapies like targeted therapy include inhibitors of the Mitogen-Activate Protein Kinase (MAPK) pathway. The cAMP pathway, and the transcription factors involved in this pathway in human melanoma, have been highlighted in resistance to RAF/MEK inhibitors. ICER, as a repressor of gene expression (an antagonist of CREB) of the cAMP pathway, might be involved in this observed resistance. In order to test this hypothesis we developed transgenic zebrafish lines expressing two different forms of ICER in the zebrafish model for melanoma, Tg(mitfa:BRAFV600E); mitfa(lf); p53(lf). The two different forms of zebrafish ICER-Iɣ were: wild-type- (wt-) and S35&41A-ICER. In S35&41A-ICER, serines 35 and 41 were substituted for alanines in order to prevent phosphorylation. We have shown before that phosphorylation on serines 41 by ERK1 was a prerequisite for polyubiquitination and proteasomal degradation, whereas phosphorylation on serine 35 by the mitotic kinase cdk1 was necessary for monoubiquitination and alter subcellular localization to the cytosol. Fish survival curves showed that ICER (wt-) form significantly accelerated melanoma onset compared to EGFP control. wt-ICER succumbed to malignancies much faster than control EGFP and S35&41A-ICER expressing fish. In contrast, the zebrafish expressing S35&41A phosphorylation mutant ICER have a significantly longer life than EGFP control. Melanocytes expressing wt- ICER grew in confluent patches in zebrafish, unlike melanocytes in the EGFP- control and S35&41A-ICER expressing zebrafish, which grew in a wild-type stripe pattern. A pathological and molecular analysis will be presented during the poster session investigating the hypothesis that this presumed paradox is related to the development of a refractory melanoma of the ICER-expressing melanocytes.