last updated April 2013
Protecting the proteins that protect the cell
The identification of a novel cancer-associated pathway could help bolster efforts to develop more effective and targeted therapeutic strategies
The protein kinase ERK transmits signals that mediate numerous essential cellular functions, and malfunctions in these pathways have been linked to a diverse array of cancers. One putative target of ERK is the transcription factor FOXO3a, a regulator of cell proliferation and a tumor suppressor, and recent work by Academia Sinica researcher Chwan-Deng Hsiao — in collaboration with an international consortium of researchers led by Mien-Chie Hung — has revealed important insights into the relationship between ERK, FOXO3a and tumor growth1.
Hung and colleagues found that ERK interacts directly with FOXO3a, introducing chemical modifications that cause the transcription factor to be exported from the nucleus. Once in the cytoplasm, FOXO3a can no longer activate its target genes, and instead it interacts with MDM2 — part of a cellular pathway that marks other proteins for prompt destruction.
The investigators found clear evidence of MDM2-mediated degradation of FOXO3a, but also found indications that this process is clinically relevant, and their analysis of tissue samples from breast cancer patients revealed a significant correlation between increased levels of MDM2 and decreased levels of FOXO3a with regard to both tumor formation and severity.
ERK is already recognized as a promising therapeutic target, but these findings indicate that bolstering FOXO3a stability could further enhance such anticancer strategies.