title: Fhit Nuclear Import Following EGF Stimulation Sustains Proliferation of Breast Cancer Cells.
abstract: The tumor-suppressor protein fragile histidine triad (Fhit) exerts its functions in the cytoplasm, although some reports suggest that it may also act in the nucleus. We previously showed that cytosolic Fhit protein levels in cancer cell lines stimulated to proliferate were reduced by proteasomal degradation. Here, we demonstrate that Fhit is physiologically present in the nucleus of breast cancer cell lines and tissues at a low level and that proliferative stimulation increases nuclear levels. Breast cancer cells expressing the FhitY114F mutant, which do not undergo proteasomal degradation, contained mutated Fhit in the nucleus, while cells treated with a proteasome inhibitor accumulated nuclear Fhit during proliferation. Thus, Fhit nuclear shuttling and proteasome degradation phenomena occur independently. When Fhit was coupled to a nuclear localization sequence, the proliferation rate of the transfected cells increased together with levels of proliferation pathway mediators cyclin D1, phospho-MAPK, and phospho-STAT3. Fhit nuclear translocation upon mitogenic stimulation may represent a new regulatory mechanism that allows rapid restoration of Fhit cytoplasmic levels and promotes the proliferation cascade activated by mitogenic stimulation.
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchi
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sasso
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Turdo
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casalini
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghirelli
authors.affiliation: Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Sfondrini
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ménard
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Campiglio
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000096:biosynthesis / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics*; D019938:Cyclin D1 / Q000096:biosynthesis; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D020929:Mitogen-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins; D046988:Proteasome Endopeptidase Complex; D050796:STAT3 Transcription Factor; D000099170:Bis(5'-adenosyl)triphosphatase; C530104:CCND1 protein, human; C494086:STAT3 protein, human