MAP3K11

Abstract: Studies examining the oncogenic or tumor suppressive functions of dysregulated microRNAs (miRs) in cancer cells may also identify novel miR targets, which can themselves serve as therapeutic targets. Using array analysis, we have previously determined that miR-199a-5p was the most downregulated miR in two esophageal cancer cell lines compared to esophageal epithelial cells. MiR-199a-5p is predicted to bind mitogen-activated protein kinase kinase kinase 11 (MAP3K11) mRNA with high affinity. In this study, we observed that MAP3K11 is markedly overexpressed in esophageal cancer cell lines. Forced expression of miR-199a-5p in these cells leads to a decrease in the mRNA and protein levels of MAP3K11, due to decreased MAP3K11 mRNA stability. A direct binding interaction between miR-199a-5p and MAP3K11 mRNA is demonstrated using biotin pull-down assays and heterologous luciferase reporter constructs and confirmed by mutational analysis. Finally, forced expression of miR-199a-5p decreases proliferation of esophageal cancer cells by inducing G2/M arrest. This effect is mediated, in part, by decreased transcription of cyclin D1, due to reduced MAP3K11-mediated phosphorylation of c-Jun. These findings suggest that miR-199a-5p acts as a tumor suppressor in esophageal cancer cells and that its downregulation contributes to enhanced cellular proliferation by targeting MAP3K11.

Abstract: // Navin Viswakarma 1 , Rakesh Sathish Nair 1 , Gautam Sondarva 1 , Subhasis Das 1 , Lucas Ibrahimi 1 , Zhiyong Chen 4 , Subhash Sinha 4 , Basabi Rana 1, 2, 3 , Ajay Rana 1, 2, 3 1 Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA 2 University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA 3 Jesse Brown VA Medical Center, Chicago, IL 60612, USA 4 Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA Correspondence to: Ajay Rana, email: arana@uic.edu Keywords: estrogen receptor, MLK3, transcriptional regulation, breast cancer, estrogen response element Received: January 30, 2017 Accepted: March 16, 2017 Published: March 25, 2017 ABSTRACT Mixed Lineage Kinase 3 (MLK3), also called as MAP3K11 is a tightly regulated MAP3K member but its cellular function is still not fully understood. Earlier we reported post-translational regulation of MLK3 by estrogen (E2) that inhibited the kinase activity and favored survival of ER + breast cancer cells. Here we report that MLK3 is also transcriptionally downregulated by E2 in ER + breast cancer cells. Publicly available data and in situ hybridization of human breast tumors showed significant down regulation of MLK3 transcripts in ER + tumors. The basal level of MLK3 transcripts and protein in ER + breast cancer cell lines were significantly lower, and the protein expression was further down regulated by E2 in a time-dependent manner. Analysis of the promoter of MLK3 revealed two ERE sites which were regulated by E2 in ER + but not in ER – breast cancer cell lines. Both ERα and ERβ were able to bind to MLK3 promoter and recruit nuclear receptor co-repressors (NCoR, SMRT and LCoR), leading to down-regulation of MLK3 transcripts. Collectively these results suggest that recruitment of nuclear receptor co-repressor is a key feature of ligand-dependent transcriptional repression of MLK3 by ERs. Therefore coordinated transcriptional and post-translational repression of pro-apoptotic MLK3 probably is one of the mechanisms by which ER + breast cancer cells proliferate and survive.