Washington: Scientists have discovered a protein involved in early steps of development of melanoma, the most deadly type of skin cancer.
Melanocytes (pigment-producing skin cells) lose the genetic regulatory mechanisms that normally limit their number, allowing them to divide and proliferate out of control.
One such regulator, called MITF, controls an array of genes that influence melanocyte development, function and survival.
Researchers at Sanford-Burnham Medical Research Institute and their collaborators recently used a melanoma mouse model, cell cultures and human tissue samples to unravel the relationship between MITF and ATF2, a transcription factor (or protein that controls gene expression) that is more active in melanomas.
The study, demonstrates that the MITF is subject to negative regulation by ATF2, and such regulation is a key determinant in melanoma development.
This work also reveals that the ratio of ATF2 to MITF in the nucleus of melanoma cells can predict survival in melanoma patients – relatively high amounts of ATF2 and correspondingly low MITF levels were associated with a poor prognosis.
Ze``ev Ronai, senior author of the study and collaborators from five medical centers in the U.S. and U.K. disrupted the ATF2 gene in the melanocytes of mice harboring mutations often seen in human melanoma.
It turns out that ATF2 blocks MITF function in the early stages of melanocyte development. Without ATF2``s foot on the brake in these mice, melanoma was inhibited thanks to its affect on MITF expression.
To determine exactly how ATF2 keeps the damper on MITF, the researchers then drilled down to melanocytes and melanoma cells in a dish.
In about half the cell lines tested, they noted that ATF2``s control over MITF is indirect – ATF2 actually controls a protein, called SOX10, which is in turn necessary for MITF expression.
The study has been published on December 23 in PLoS Genetics.