title: MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop.
abstract: Signal transducer and activator of transcription 3 (STAT3) is activated in human breast cancer and other malignancies. Mucin 1 (MUC1) is a heterodimeric cell surface glycoprotein that is overexpressed in human carcinomas and, like STAT3, promotes cell survival and induces transformation. We found that in breast cancer cells, the MUC1 carboxyl-terminal receptor subunit (MUC1-C) associates with the gp130-Janus-activated kinase 1 (JAK1)-STAT3 complex. The MUC1-C cytoplasmic domain interacted directly with JAK1 and STAT3, and MUC1-C was necessary for JAK1-mediated STAT3 activation. In turn, MUC1-C and activated STAT3 occupied the promoter of MUC1, and MUC1-C contributed to STAT3-mediated activation of MUC1 transcription. The MUC1-C inhibitor GO-201 blocked the MUC1-C interaction with STAT3, thereby decreasing MUC1-C and STAT3 occupancy on the MUC1 and STAT3 promoters and activation of STAT3 target genes, including MUC1 itself. These findings indicate that MUC1-C promotes STAT3 activation and that MUC1-C and STAT3 function in an autoinductive loop that may play a role in cancer cell survival.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rehan
authors.initials: R
authors.lastname: Ahmad
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.forename: Michio
authors.initials: M
authors.lastname: Kosugi
authors.forename: Maya Datt
authors.initials: MD
authors.lastname: Joshi
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.forename: Baldev
authors.initials: B
authors.lastname: Vasir
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawano
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C549568:GO 201; D015850:Interleukin-6; C060192:MUC1 protein, human; D018396:Mucin-1; D046912:Multiprotein Complexes; D010455:Peptides; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D008156:Luciferases; C507904:JAK1 protein, human; D053613:Janus Kinase 1