The transformation of normal melanocytes into melanoma
Summary
This project investigates the role of the oncogenes Ras and Braf and the tumour suppressors p16INK4a, p14ARF, p53 and PTEN in the malignant transformation of melanocytes.
Supervisor(s)
Research Location
Westmead - Westmead Institute for Medical Research
Program Type
Masters/PHD
Synopsis
The cell cycle research group investigates the biomolecular mechanisms of melanomagenesis. Our main focus is to investigate the function of the tumour suppressor products of the INK4a/ARF locus, which displays germline mutations in 39% of melanoma-prone families. This locus encodes the melanoma associated tumour suppressor proteins, p16INK4a and p14ARF. Thus, many melanoma-prone individuals express both wild type and mutant forms of these proteins, and the impact of this heterozygous state is being investigated. In particular, we are establishing critical melanoma models to define whether accumulation of mutant proteins alters the function of their wild type counterparts. Both the p16INK4a and p14ARF proteins inhibit cell proliferation and induce of a tumour suppressive “senescent” state, that potentially protects melanocytes from oncogene induced transformation . The aberrant activation of the N-RAS and BRAF oncogenes in melanocytes can trigger a growth arrest response, that is bypassed by additional genetic alterations. We are currently investigating the mechanisms responsible for this growth arrest response, which is clearly critical in protecting against melanoma formation in sun-exposed skin. Our research efforts into the biomolecular pathways that link p16INK4a and p14ARF to melanoma are aimed towards finding biomolecular targets for melanoma therapy in the future. To date such therapy is completely bereft of successful strategies once the disease has reached the metastatic state.
Additional Information
Our research involves a variety of molecular and tissue culture techniques such as cloning of genes into mammalian expression vectors, transfection, Western analysis, immunocyto-staining, culture of tumour cell lines and primary cells (2D and 3D culture), transfection, lentiviral gene transfer, real time PCR, FACS analysis and more. Current projects are: Molecular determinants of escape from BRAF-induced human melanocyte senescence in the genesis and targeted control of melanoma.
- This project involves lentiviral transfer of oncogenes or lentiviral silencing to clarify whether p16INK4a and p14ARF protect from melanoma genesis.
- This project will investigate a possible dominant negative effect of mutant p16INK4a on the wild type protein.
- This project clarified that while p14ARF alone does not cause apoptosis, it leads to increased cell death in combination with certain cytotoxic drugs.
- We have recently identified a novel sumoylation function through which ARF may exert its cell cycle inhibitory and tumour suppressor functions. This function is being investigated and new p14ARF sumoylation targets are being identified.
- We have recently identified a novel binding partner of p16INK4a and our data show that it co-operates with p16INK4a in cell cycle regulation.
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Keywords
Cutaneous melanoma, melanoma, p16INK4a, p14ARF, p53, PTEN, N-Ras, Braf, cell cycle, senescence, Cell biology, Genes in biology & medicine
Opportunity ID
The opportunity ID for this research opportunity is: 219