Oncogenic protein MTBP interacts with MYC to promote tumorigenesis.
Despite its involvement in most human cancers, MYC continues to pose a challenge as a readily tractable therapeutic target. Here we identify the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of Mdm2-binding protein (MTBP), a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC at promoters and increased MYC-mediated transcription, proliferation, neoplastic transformation, and tumor development. In breast cancer specimens, we determined overexpression of both MYC and MTBP was associated with a reduction in 10-year patient survival compared with MYC overexpression alone. MTBP was also frequently co-amplified with MYC in many human cancers. Mechanistic investigations implicated associations with TIP48/TIP49 as well as MYC in MTBP function in cellular transformation and the growth of human breast cancer cells. Taken together, our findings show MTBP functions with MYC to promote malignancy, identifying this protein as a novel general therapeutic target in human cancer.
Authors' Affiliations: Departments of Pathology, Microbiology and Immunology and.
Brian C
BC
Grieb
Authors' Affiliations: Departments of Pathology, Microbiology and Immunology and.
Mark W
MW
Gramling
Authors' Affiliations: Departments of Pathology, Microbiology and Immunology and.
Maria Pia
MP
Arrate
Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee;
Xi
X
Chen
Department of Biochemistry, Temple University; Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania; and.
Stephen L
SL
Beauparlant
Department of Biochemistry, Temple University; Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania; and.
Dale S
DS
Haines
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania; and Department of Physiology, Michigan State University, East Lansing, Michigan.
Hua
H
Xiao
Authors' Affiliations: Departments of Pathology, Microbiology and Immunology and christine.eischen@vanderbilt.edu.
Christine M
CM
Eischen
D016475:3T3 Cells; D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D002352:Carrier Proteins; C485931:MTBP protein, human; D016271:Proto-Oncogene Proteins c-myc; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human; C122079:RUVBL2 protein, human