title: Transcriptional regulation of mixed lineage kinase 3 by estrogen and its implication in ER-positive breast cancer pathogenesis.
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.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Navin
authors.initials: N
authors.lastname: Viswakarma
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Rakesh Sathish
authors.initials: RS
authors.lastname: Nair
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sondarva
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Subhasis
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Ibrahimi
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Subhash
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.|University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.|Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
authors.forename: Basabi
authors.initials: B
authors.lastname: Rana
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.|University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.|Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Rana
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D004967:Estrogens; D020930:MAP Kinase Kinase Kinases; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
keywords: MLK3; breast cancer; estrogen receptor; estrogen response element; transcriptional regulation