title: Hsp70-Bag3 interactions regulate cancer-related signaling networks.
abstract: Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts. Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Colvin
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Gabai
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Gong
authors.affiliation: Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Calderwood
authors.affiliation: Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Suryaram
authors.initials: S
authors.lastname: Gummuluru
authors.affiliation: Medical Radiology Research Center, Obninsk, Russia.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Matchuk
authors.affiliation: Medical Radiology Research Center, Obninsk, Russia.
authors.forename: Svetlana G
authors.initials: SG
authors.lastname: Smirnova
authors.affiliation: Medical Radiology Research Center, Obninsk, Russia.
authors.forename: Nina V
authors.initials: NV
authors.lastname: Orlova
authors.affiliation: Medical Radiology Research Center, Obninsk, Russia.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Zamulaeva
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Mikel
authors.initials: M
authors.lastname: Garcia-Marcos
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
authors.forename: Z T
authors.initials: ZT
authors.lastname: Young
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Rauch
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California. sherma1@bu.edu jason.gestwicki@ucsf.edu takayama@bu.edu.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, Massachusetts. sherma1@bu.edu jason.gestwicki@ucsf.edu takayama@bu.edu.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takayama
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts. sherma1@bu.edu jason.gestwicki@ucsf.edu takayama@bu.edu.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Sherman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D051959:ELAV Proteins / Q000235:genetics; D000067780:ELAV-Like Protein 1; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics; D045325:HCT116 Cells; D057809:HEK293 Cells; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D061986:MCF-7 Cells; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D000077022:Survivin; D014157:Transcription Factors / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D050884:HSP72 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D000077022:Survivin; D014157:Transcription Factors