MEKK1 is a Novel Regulator of the Dmp1-Arf-p53 Pathway and Prognostic Indicator in Breast Cancer
Abstract : Breast cancer is the most common malignancy in women. Selection of patients for personalized therapy based on a risk-benefit assesment has not been improved. Dmp1 is a tumor suppressor that activates the p14ARF-p53 pathway to prevent breast cancer development. Regulation of Dmp1 at a transcription level by oncogenes is well understood; however, the role of Dmp1 phosphorylation is unknown. We identify a serine/threonine kinase of the MAPK pathway, MEKK1, which directly phosphorylates Dmp1. MEKK1 phosphorylates Dmp1 on multiple Serine/Threonines residues. Dmp1 and MEKK1 synergize on the Arf transactivation and the p53 pathway induction. Expression of MEKK1 in breast cancer cell lines leads to accumulation of ARF, p53, and p53 target genes. Analysis of MEKK1 locus in human breast tumor samples reveled that MEKK1 is frequently deleted and low expression of MEKK1 may be a new prognostic indicator of patient outcome.