title: Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif.
abstract: The MYC family of oncogenes encodes a set of three related transcription factors that are overexpressed in many human tumors and contribute to the cancer-related deaths of more than 70,000 Americans every year. MYC proteins drive tumorigenesis by interacting with co-factors that enable them to regulate the expression of thousands of genes linked to cell growth, proliferation, metabolism and genome stability. One effective way to identify critical co-factors required for MYC function has been to focus on sequence motifs within MYC that are conserved throughout evolution, on the assumption that their conservation is driven by protein-protein interactions that are vital for MYC activity. In addition to their DNA-binding domains, MYC proteins carry five regions of high sequence conservation known as Myc boxes (Mb). To date, four of the Mb motifs (MbI, MbII, MbIIIa and MbIIIb) have had a molecular function assigned to them, but the precise role of the remaining Mb, MbIV, and the reason for its preservation in vertebrate Myc proteins, is unknown. Here, we show that MbIV is required for the association of MYC with the abundant transcriptional coregulator host cell factor-1 (HCF-1). We show that the invariant core of MbIV resembles the tetrapeptide HCF-binding motif (HBM) found in many HCF-interaction partners, and demonstrate that MYC interacts with HCF-1 in a manner indistinguishable from the prototypical HBM-containing protein VP16. Finally, we show that rationalized point mutations in MYC that disrupt interaction with HCF-1 attenuate the ability of MYC to drive tumorigenesis in mice. Together, these data expose a molecular function for MbIV and indicate that HCF-1 is an important co-factor for MYC.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Thomas
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Foshage
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Weissmiller
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Vanderbilt International Scholar Program, Vanderbilt University, Nashville, TN, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Popay
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Grieb
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Qualls
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: V
authors.initials: V
authors.lastname: Ng
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Carboneau
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lorey
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Eischen
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: W P
authors.initials: WP
authors.lastname: Tansey
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D057809:HEK293 Cells; D051863:Host Cell Factor C1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc