Myc 9aaTAD activation domain binds to mediator of transcription
with superior high affinity

J 2024

Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity

KNIGHT, Andrea, Josef HOUSER, Tomáš OTAŠEVIČ, Vilém JURÁŇ, Václav VYBÍHAL et. al.

Basic information

Original name

Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity

Authors

KNIGHT, Andrea (203 Czech Republic, belonging to the institution), Josef HOUSER (203 Czech Republic, belonging to the institution), Tomáš OTAŠEVIČ (203 Czech Republic, belonging to the institution), Vilém JURÁŇ (203 Czech Republic, belonging to the institution), Václav VYBÍHAL (203 Czech Republic, belonging to the institution), Martin SMRČKA (203 Czech Republic, belonging to the institution) and Martin PISKÁČEK (203 Czech Republic, belonging to the institution)

Edition

Molecular Medicine, New York, SPRINGER, 2024, 1076-1551

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

is not subject to a state or trade secret

References:

URL

Impact factor

Impact factor: 6.000 in 2023

RIV identification code

RIV/00216224:14110/24:00137688

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1186/s10020-024-00896-7

UT WoS

001354434200004

EID Scopus

2-s2.0-85209214494

Keywords in English

9aaTAD; Myc; MycN; KIX; CBP

Abstract

V originále

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.

Links

NV19-05-00410, research and development project

Name: Úloha cytotoxických gamma-delta T buněk na terapeutické rezistenci a recidivě Glioblastoma Multiforme

Investor: Ministry of Health of the CR

90127, large research infrastructures

Name: CIISB II

Cite

KNIGHT, Andrea, Josef HOUSER, Tomáš OTAŠEVIČ, Vilém JURÁŇ, Václav VYBÍHAL, Martin SMRČKA and Martin PISKÁČEK. Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity. Molecular Medicine. New York: SPRINGER, 2024, vol. 30, No 1, p. 1-9. ISSN 1076-1551. Available from: https://dx.doi.org/10.1186/s10020-024-00896-7.

@article{2453278,
   author = {Knight, Andrea and Houser, Josef and Otaševič, Tomáš and Juráň, Vilém and Vybíhal, Václav and Smrčka, Martin and Piskáček, Martin},
   article_location = {New York},
   article_number = {1},
   doi = {http://dx.doi.org/10.1186/s10020-024-00896-7},
   keywords = {9aaTAD; Myc; MycN; KIX; CBP},
   language = {eng},
   issn = {1076-1551},
   journal = {Molecular Medicine},
   title = {Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity},
   url = {https://molmed.biomedcentral.com/articles/10.1186/s10020-024-00896-7},
   volume = {30},
   year = {2024}
}

TY  - JOUR
ID  - 2453278
AU  - Knight, Andrea - Houser, Josef - Otaševič, Tomáš - Juráň, Vilém - Vybíhal, Václav - Smrčka, Martin - Piskáček, Martin
PY  - 2024
TI  - Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity
JF  - Molecular Medicine
VL  - 30
IS  - 1
SP  - 1-9
EP  - 1-9
PB  - SPRINGER
SN  - 10761551
KW  - 9aaTAD
KW  - Myc
KW  - MycN
KW  - KIX
KW  - CBP
UR  - https://molmed.biomedcentral.com/articles/10.1186/s10020-024-00896-7
N2  - 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.
ER  -

KNIGHT, Andrea, Josef HOUSER, Tomáš OTAŠEVIČ, Vilém JURÁŇ, Václav VYBÍHAL, Martin SMRČKA and Martin PISKÁČEK. Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity. \textit{Molecular Medicine}. New York: SPRINGER, 2024, vol.~30, No~1, p.~1-9. ISSN~1076-1551. Available from: https://dx.doi.org/10.1186/s10020-024-00896-7.

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