Study identifies protein kinase C-epsilon as a molecular switch that determines tumor-promoting or -suppressing activity in skin cells
The National Cancer Institute (NCI) estimates that as many as one in 51 men and women will be diagnosed with melanoma-the deadliest form of skin cancer-at some point during their lifetimes. A research team led by Ze'ev Ronai, Ph.D. at Sanford-Burnham Medical Research Institute (Sanford-Burnham) is working to unravel the molecular mechanisms underlying the development and progression of this disease in hopes of improving prevention and treatment strategies. To do this, Ronai's laboratory has been studying a protein named Activating Transcription Factor 2 (ATF2), which is associated with poor prognosis in melanoma. ATF2 is a two-faced protein-in melanoma cells, it's oncogenic, or cancer-causing, while in non-malignant types of skin cancers, it acts as a tumor suppressor. In a paper published February 3 in the journal Cell, the team identified a molecular switch that controls ATF2's dual functions. This switch is controlled by protein kinase Cε (PKCε), which disables ATF2's tumor-suppressing activities, sensitizing cells to chemotherapy; instead, ATF2's tumor-promoting activity is enhanced. The team also found that high levels of PKCε in melanoma are associated with poor prognosis.
"PKCε is the culprit behind melanoma's 'oncogenic addiction,'" said Ronai, associate director of the Sanford-Burnham's NCI-designated Cancer Center and senior author of the study. "ATF2 is normally a 'good guy.' But when there is too much PKCε-as in malignant melanoma-ATF2 becomes an oncogene, promoting tumor development."
In this study, Ronai and lead author Eric Lau, Ph.D., a postdoctoral researcher in his lab, found that PKCε's malignant power is in its ability to direct ATF2's location and activity within a cell. In a normal cell, PKCε modifies ATF2, keeping it in the nucleus, where it turns genes on and off and helps repair damaged DNA. When the cell experiences exposure to toxicity or stress (radiation, for example), PKCε backs off and ATF2 is able to move out of the nucleus and to the mitochondria, the part of the cell that generates energy and helps control cellular life and death. When it gets there, ATF2 helps to set the cell on a death course-a safeguard cells use to prevent errors that often make them cancerous.