title: RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export.
abstract: Chromosome region maintenance 1-mediated nucleocytoplasmic transport has been shown as a potential anticancer target in various malignancies. However, the role of the most characterized chromosome region maintenance 1 cofactor ran binding protein 3 (RanBP3) in cancer cell biology has never been investigated. Utilizing a loss-of-function experimental setting in a vast collection of genetically varied melanoma cell lines, we observed the requirement of RanBP3 in melanoma cell proliferation and survival. Mechanistically, we suggest the reinstatement of transforming growth factor-β (TGF-β)-Smad2/3-p21(Cip1) tumor-suppressor axis as part of the RanBP3 silencing-associated antiproliferative program. Employing extensive nuclear export sequence analyses and immunofluorescence-based protein localization studies, we further present evidence suggesting the requirement of RanBP3 function for the nuclear exit of the weak nuclear export sequence-harboring extracellular signal-regulated kinase protein, although it is dispensable for general CRM1-mediated nuclear export of strong nuclear export sequence-harboring cargoes. Rendering mechanistic support to RanBP3 silencing-mediated apoptosis, consequent to extracellular signal-regulated kinase nuclear entrapment, we observed increased levels of cytoplasmically restricted nonphosphorylated/active proapoptotic Bcl-2-antagonist of cell death (BAD) protein. Last, we present evidence suggesting the frequently activated mitogen-activated protein kinase signaling in melanoma as a potential founding basis for a deregulated post-translational control of RanBP3 activity. Collectively, the presented data suggest RanBP3 as a potential target for therapeutic intervention in human melanoma.
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria; Biochemical-Pharmacological Center, University of Marburg, Marburg, Germany. Electronic address: pathria@staff.uni-marburg.de.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Pathria
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Bhavuk
authors.initials: B
authors.lastname: Garg
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Wagner
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Kanika
authors.initials: K
authors.lastname: Garg
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gschaider
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Jalili
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: stephan.wagner@meduniwien.ac.at.
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Wagner
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics*; D011485:Protein Binding; D034622:RNA Interference; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D028884:Karyopherins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; C112820:RANBP3 protein, human