Scientists use the zebrafish to gain insight into the development of melanoma
Melanocytes are pigment cells located in the bottom layer (the stratum basale) of the skin’s epidermis, the middle layer of the eye (the uvea), the inner ear, meninges, bones and heart.
Oncogene: An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell. Many cells normally undergo a programmed form of death. Activated oncogenes can cause those cells to survive and proliferate instead. Most oncogenes require an additional step, such as mutations in another gene, or environmental factors, such as viral infection, to cause cancer.
RAS: The first oncogene isolated was from a human bladder tumor. The gene isolated from the bladder tumor was almost identical to the normal human gene and almost identical to the gene that was present in the tumor virus that infected rodents. This gene has become known as “RAS,” because it was originally isolated from rats with sarcoma. And the only really significant difference between the normal human gene, the bladder tumor gene, and the rodent virus gene was a change in one codon, Codon XII, i.e. a change in amino acids. Mutations in RAS are known to lead to cancer. In some cases, the type of RAS mutation is a predictor of a patient’s response to treatment and their overall prognosis.
Proto-oncogene: A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression.
Transcription factor: In the field of molecular biology, a transcription factor (sometimes called a sequence-specific DNA binding factor) is a protein that binds to specific DNA sequences and thereby controls the transfer (or transcription) of genetic information from DNA to RNA. Transcription factors perform this function alone or with other proteins in a complex, by promoting (as an activator), or blocking (as a repressor) the recruitment of RNA polymerase (the enzyme which performs the transcription of genetic information from DNA to RNA) to specific genes. A defining feature of transcription factors is that they contain one or more DNA binding domains (DBDs) which attach to specific sequences of DNA adjacent to the genes that they regulate.
Melanoma is a malignant tumor of melanocytes in skin. It is one of the rarer types of skin cancer but causes the majority of skin cancer related deaths. Malignant melanoma is a serious type of skin cancer. It is due to uncontrolled growth of melanocytes. At present the treatment includes surgical removal of the tumor, adjuvant treatment, chemo- and immunotherapy, or radiation therapy. According to a WHO report about 48,000 melanoma related deaths occur worldwide per year. Malignant melanoma accounts for 75 percent of all deaths associated with skin cancer.
Generally, an individual’s risk for developing melanoma depends on two groups of factors: intrinsic and environmental. “Intrinsic” factors are generally an individual’s family history and inherited genotype, while the most relevant environmental factor is sun exposure. Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell’s genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of Activating Transcription Factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells. Occasional extreme sun exposure (resulting in “sunburn”) is related to melanoma.
Scientists use the zebrafish to gain insight into the development of melanoma
Scientists at the University of Manchester in England and the University Hospital Zürich in Switzerland use the zebrafish to gain insight into the influence of known cancer genes on the development and progression of melanoma.
Zebrafish are a useful tool to understand human disease because they are small, transparent, and easy to propagate and maintain. Tumors created from the pigmented cells of zebrafish, known as melanocytes, are easy to see against their thin, light colored bodies. The research team notes that these fish may be a useful experimental tool for human disease.
Zebrafish
The researchers generated several zebrafish with changes in RAS or other RAS-regulated proteins to create a useful model that can be used to study and understand human melanoma. Many of the changes they made caused melanoma in the zebrafish, indicating that zebrafish respond similarly to changes in these signals as do humans. Zebrafish that were born from the original mutant fish displayed abnormal growth of their melanocytes, reminiscent of familial atypical mole and melanoma syndrome (FAMM) seen in humans. By producing other signaling molecules in the mutant fish, the researchers were able to identify a pathway that reduced the effects of RAS mutations on melanoma progression in zebrafish.
Source: http://dmm.biologists.org/
May 26, 2009