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Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity
A. Knight, J. Houser, T. Otasevic, V. Juran, V. Vybihal, M. Smrcka, M. Piskacek
Language English Country England, Great Britain
Document type Journal Article
Grant support
NV19-05-00410
Ministerstvo Vnitra České Republiky
NLK
BioMedCentral
from 1994-11-01
BioMedCentral Open Access
from 2018
Directory of Open Access Journals
from 2000
Free Medical Journals
from 1994
PubMed Central
from 1994
Europe PubMed Central
from 1994
ProQuest Central
from 2011-01-01
Open Access Digital Library
from 2000-01-01
Medline Complete (EBSCOhost)
from 2007-09-01
Health & Medicine (ProQuest)
from 2011-01-01
ROAD: Directory of Open Access Scholarly Resources
from 1994
Springer Nature OA/Free Journals
from 1994-11-01
- MeSH
- Transcriptional Activation MeSH
- Humans MeSH
- Protein Domains MeSH
- Proto-Oncogene Proteins c-myc * metabolism genetics MeSH
- Amino Acid Sequence MeSH
- Protein Binding * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The overexpression of MYC genes is frequently found in many human cancers, including adult and pediatric malignant brain tumors. Targeting MYC genes continues to be challenging due to their undruggable nature. Using our prediction algorithm, the nine-amino-acid activation domain (9aaTAD) has been identified in all four Yamanaka factors, including c-Myc. The predicted activation function was experimentally demonstrated for all these short peptides in transactivation assay. We generated a set of c-Myc constructs (1-108, 69-108 and 98-108) in the N-terminal regions and tested their ability to initiate transcription in one hybrid assay. The presence and absence of 9aaTAD (region 100-108) in the constructs strongly correlated with their activation functions (5-, 3- and 67-times respectively). Surprisingly, we observed co-activation function of the myc region 69-103, called here acetyl-TAD, previously described by Faiola et al. (Mol Cell Biol 25:10220-10234, 2005) and characterized in this study as a new domain collaborating with the 9aaTAD. We discovered strong interactions on a nanomolar scale between the Myc-9aaTAD activation domains and the KIX domain of CBP coactivator. We showed conservation of the 9aaTADs in the MYC family. In summary for the c-Myc oncogene, the acetyl-TAD and the 9aaTAD domains jointly mediated activation function. The c-Myc protein is largely intrinsically disordered and therefore difficult to target with small-molecule inhibitors. For the c-Myc driven tumors, the strong c-Myc interaction with the KIX domain represents a promising druggable target.
References provided by Crossref.org
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- $a The overexpression of MYC genes is frequently found in many human cancers, including adult and pediatric malignant brain tumors. Targeting MYC genes continues to be challenging due to their undruggable nature. Using our prediction algorithm, the nine-amino-acid activation domain (9aaTAD) has been identified in all four Yamanaka factors, including c-Myc. The predicted activation function was experimentally demonstrated for all these short peptides in transactivation assay. We generated a set of c-Myc constructs (1-108, 69-108 and 98-108) in the N-terminal regions and tested their ability to initiate transcription in one hybrid assay. The presence and absence of 9aaTAD (region 100-108) in the constructs strongly correlated with their activation functions (5-, 3- and 67-times respectively). Surprisingly, we observed co-activation function of the myc region 69-103, called here acetyl-TAD, previously described by Faiola et al. (Mol Cell Biol 25:10220-10234, 2005) and characterized in this study as a new domain collaborating with the 9aaTAD. We discovered strong interactions on a nanomolar scale between the Myc-9aaTAD activation domains and the KIX domain of CBP coactivator. We showed conservation of the 9aaTADs in the MYC family. In summary for the c-Myc oncogene, the acetyl-TAD and the 9aaTAD domains jointly mediated activation function. The c-Myc protein is largely intrinsically disordered and therefore difficult to target with small-molecule inhibitors. For the c-Myc driven tumors, the strong c-Myc interaction with the KIX domain represents a promising druggable target.
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