Inhibition of Myc transcriptional activity by a mini-protein based upon Mxd1.
Amino Acid Sequence
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
/ chemistry
Basic-Leucine Zipper Transcription Factors
/ metabolism
Cell Line
Cell Nucleolus
/ metabolism
Cell Nucleus
/ metabolism
Cell Proliferation
/ drug effects
Humans
Peptide Fragments
/ chemistry
Pol1 Transcription Initiation Complex Proteins
/ metabolism
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myc
/ antagonists & inhibitors
Repressor Proteins
/ chemistry
Transcription, Genetic
/ drug effects
Max
Myc
Myc inhibitors
Omomyc
cancer
oncogene
Journal
FEBS letters
ISSN: 1873-3468
Titre abrégé: FEBS Lett
Pays: England
ID NLM: 0155157
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
13
11
2019
revised:
07
02
2020
accepted:
10
02
2020
pubmed:
14
2
2020
medline:
6
5
2021
entrez:
14
2
2020
Statut:
ppublish
Résumé
Myc, a transcription factor with oncogenic activity, is upregulated by amplification, translocation, and mutation of the cellular pathways that regulate its stability. Inhibition of the Myc oncogene by various modalities has had limited success. One Myc inhibitor, Omomyc, has limited cellular and in vivo activity. Here, we report a mini-protein, referred to as Mad, which is derived from the cellular Myc antagonist Mxd1. Mad localizes to the nucleus in cells and is 10-fold more potent than Omomyc in inhibiting Myc-driven cell proliferation. Similar to Mxd1, Mad also interacts with Max, the binding partner of Myc, and with the nucleolar upstream binding factor. Mad binds to E-Box DNA in the promoters of Myc target genes and represses Myc-mediated transcription to a greater extent than Omomyc. Overall, Mad appears to be more potent than Omomyc both in vitro and in cells.
Identifiants
pubmed: 32053209
doi: 10.1002/1873-3468.13759
doi:
Substances chimiques
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
0
Basic-Leucine Zipper Transcription Factors
0
MXD1 protein, human
0
Myc associated factor X
0
Peptide Fragments
0
Pol1 Transcription Initiation Complex Proteins
0
Proto-Oncogene Proteins c-myc
0
Repressor Proteins
0
transcription factor UBF
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1467-1476Informations de copyright
© 2020 Federation of European Biochemical Societies.
Références
Meyer N and Penn LZ (2008) Reflecting on 25 years of Myc. Nat Rev Cancer 8, 976-990.
Wasylishen AR and Penn LZ (2010) Myc: the beauty and the beast. Genes Cancer 1, 532-541.
Dang CV (2012) MYC on the path to cancer. Cell 149, 22-35.
Kato GJ, Barret J, Villa-Garcia M and Dang CV (1990) An amino terminal c-Myc domain required for neoplastic transformation activates transcription. Mol Cell Biol 10, 5914-5920.
Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN and Weintraub H (1990) Sequence specific DNA binding by c-Myc protein. Science 250, 1149-1151.
Halazonetis TD and Kandil AN (1991) Determination of the c-MYC DNA-binding site. Proc Nat Acad Sci USA 88, 6162-6166.
Blackwood EM and Eisenman RN (1991) Max: a helix-loop-helix protein that forms a sequence specific DNA-binding complex with Myc. Science 251, 1211-1217.
Conacci-Sorrell M, McFerrin L and Eisenmann RN (2014) An overview of MYC and its interactome. Cold Spring Harb Perspect 4, a014357.
Diolati D, McFerrin L, Carroll PA and Eisenmann RN (2015) Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis. Biochim Biophys Acta 1849, 484-500.
Ayer DE, Lawerence QA and Eisenmann RN (1995) Mad-max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell 80, 767-776.
Lusher B (2012) MAD1 and its life as a MYC antagonist: an update. Eur J Cell Biol 91, 505-514.
Yang G and Hurlin PJ (2017) MNT and emerging concepts of MNT-MYC antagonism. Genes 8, 83-95.
Carroll PA, Diolaiti D, McFerrin L, Gu H, Djukovic D, Du J, Cheng PF, Anderson S, Ulrich M, Hurley JB et al. (2015). Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorgenesis. Cancer Cell 27, 271-285.
Grinberg AV, Hu CD and Kerpola TK (2004) Visualization of Myc/Max/Mxd family dimers and the competition for dimerization in living cells. Mol Cell Biol 24, 4294-4308.
Grandori C, Gomez-Roman N, Felton-Edkins ZA, Ngouenet C, Galloway DA, Eisenman RN and White RJ (2005) c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol 7, 311-318.
Lafita-Navarro M, Bianco R, Mata-Garrido J, Liano-Pons J, Tapia O, Garcia-Gutierrez L, García-Alegría E, Berciano MT, Lafarga M and León J (2016) MXD1 localizes in the nucleolus, binds UBF, and impairs rRNA synthesis. Oncotarget 7, 69536-69548.
Poortengs G, Hannan KJ, Snelling H, Walkley C, Jenkins A, Sharkey K, Wall M, Brandenburger Y, Palatsides M, Pearson RB et al. (2004) Mad1 and c-Myc regulate UBF and rDNA transcription during granulocyte differentiation. EMBO J 23, 3325-3335.
Xu L, Zhu J, Hu X, Zhu H, Kim HT, LaBear J, Goldberg A and Yuan J (2007) cIAP cooperates with Myc by acting as a ubiquitin ligase for Mad1. Mol Cell 28, 914-922.
Zhu J, Blenis J and Yuan J (2008) Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc Natl Acad Sci USA 105, 6584-6589.
Xu J, Chen G, DeJong AT, Shahraven SH and Shin JA (2009) Max-E47, a designed minamilist protein that targets the E-box DNA in vivo and in vitro. J Am Chem Soc 131, 7839-7848.
Lustig LC, Dingar WB, Lourenco C, Kalkat M, Ponzielli R, Chan WCW and Penn LZ (2017) Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumor xenograft growth. Oncogene 36, 6830-6837.
Strunz NB, Chen A, Deutzman A, Wilson RM, Stefan E, Evans HL, Ramirez MA, Liang T, Caballero F, Wildschut MHE et al. (2019) Stabilization of the Max homodimer by a small molecule attenuates Myc driven transcription. Cell Chem Biol 26, 711-723.
Li H, Fang Y, Niu C, Cao H, Mi T, Zhu H, Yuan J and Zhu J (2018) Inhibition of c-IAP1 as a strategy for targeting c-Myc-driven oncogenic activity. Proc Natl Acad Sci USA 115, E9317-E9324.
Soucek L, Helmer-Citterich M, Sacco A, Jucker R, Cesareni G and Nasi S (1998) Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene 17, 2463-2472.
Savino M, Annibali D, Carucci N, Favuzzi E, Cole MD, Evan GI, Soucek L and Nasi S (2011) The action mechanism of the Myc inhibitor termed omomyc may give clues on how to target Myc for cancer therapy. PLoS ONE 6, e22284.
Jung LA, Gebhardt A, Koelmer W, Ade CP, Walz S, Kuper J, von Eyss B, Letschert S, Redel C, d'Artista L et al. (2017) OmoMYC blunts promoter invasion by oncogenic Myc to inhibit gene expression characteristic of Myc-dependent tumors. Oncogene 36, 1911-1924.
Beaulieu M-E, Jausset T, Masso-Valles D, Martinez-Martin S, Rahl P, Maltais L, Zacarias-Fluck MF, Casacuberta-Serra S, Serrano Del Pozo E, Fiore C et al. (2019) Intrinsic cell-penetrating activity propels proof of concept to viable anti-MYC therapy. Sci Transl Med 11, eaar 5013.
Demma MJ, Mapelli C, Sun A, Bodea S, Rupercht B, Javaid S, Wiswell D, Muise E, Chen S, Zelina J et al. (2019) Omomyc reveals new mechanisms to inhibit the MYC oncogene. Mol Cell Biol 39, e00248-19.
Yin X, Giap C, Lazo JS and Prochownik EV (2003) Low molecular weight inhibitors of Myc-max and function. Oncogene 22, 6151-6159.
Choi SH, Mahankail M, Lee SJ, Hull M, Petrassi HM, Chatterjee AK, Schultz PG, Jones KA and Shen W (2017) Targeted disruption of the Myc-max oncoprotein by a small molecule. ACS Chem Biol 12, 2715-2719.