Thesis
Melanosome-related proteins VPS16, VPS11, OCA2, and MITFA, are required for chemotherapy drug resistance in Zebrafish melanophores
Washington State University
Master of Science (MS), Washington State University
05/2016
Handle:
https://hdl.handle.net/2376/101530
Abstract
Human melanoma, when compared to other forms of cancer, is unusually resistant to drug treatment. This cancer occurs in melanocytes--highly pigmented cells that possess mature pigment-producing vesicles (melanosomes). Recent studies have shown that the drug sensitivity of melanoma cells can be dramatically increased by blocking the full development and function of melanosomes. The current hypothesis, supported by these studies, is that melanosomes contribute to drug resistance by sequestering the drug and therefore keeping it from reaching the nucleus within the cancer cell. Melanosomes complete four stages of development and it is believed that only mature melanosomes in the final two stages can sequester drug. Therefore, inhibiting melanosome development may result in a decrease in chemotherapy drug resistance in pigment cells. Here, we test this hypothesis in vivo and investigate which proteins required for melanosome development (biogenesis) are most critical to chemotherapy drug resistance. We have chosen the following protein targets: Mitfa (microphthalmia-associated transcription factor), which controls melanocyte differentiation and regulates expression of several melanosome structural proteins; Vps11 and Vps16 (vacuole protein sorting), members of the HOPS complex which facilitates transport of biogenesis proteins to the melanosome; and Oca2 (oculocutaneous albinism 2), an ion channel which maintains acidity in melanosomes, allowing the production of melanin. Our lab has identified and characterized two zebrafish lines with confirmed mutations in vps11 and oca2. We obtained a confirmed mitfa mutant line from another lab. We are currently working to verify the mutation in a fourth zebrafish line which has a probable mutation in vps16 as shown by gene mapping and comparison to the vps11 mutant. When fish from these four mutant lines are exposed to chemotherapeutic drug, cisplatin, a significant drop in their melanophore (homologous to human melanocytes) number compared to the wildtype control is observed, with the oca2 mutation having the greatest effect. This increase in drug sensitivity was melanophore specific. This is the first in vivo study to show an increase in chemotherapeutic drug sensitivity when melanosome-related mutations were present. The proteins tested are novel drug target possibilities for a treatment to increase melanoma sensitivity to chemotherapy drugs.
Metrics
5 File views/ downloads
47 Record Views
Details
- Title
- Melanosome-related proteins VPS16, VPS11, OCA2, and MITFA, are required for chemotherapy drug resistance in Zebrafish melanophores
- Creators
- Kersten Anne Peterson
- Contributors
- Cynthia D. Cooper (Chair)Allison Coffin (Committee Member) - Washington State University, Integrative Physiology and Neuroscience, Department ofChristine Portfors (Committee Member) - Washington State University, Office of the ProvostGrant D Trobridge (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Biological Sciences, School of
- Theses and Dissertations
- Master of Science (MS), Washington State University
- Publisher
- Washington State University; [Pullman, Washington] :
- Number of pages
- 38
- Identifiers
- 99900525023301842
- Language
- English
- Resource Type
- Thesis