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.

Základní údaje

Originální název

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

Autoři

KNIGHT, Andrea (203 Česká republika, domácí), Josef HOUSER (203 Česká republika, domácí), Tomáš OTAŠEVIČ (203 Česká republika, domácí), Vilém JURÁŇ (203 Česká republika, domácí), Václav VYBÍHAL (203 Česká republika, domácí), Martin SMRČKA (203 Česká republika, domácí) a Martin PISKÁČEK (203 Česká republika, domácí)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.000 v roce 2023

Kód RIV

RIV/00216224:14110/24:00137688

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

001354434200004

EID Scopus

2-s2.0-85209214494

Klíčová slova anglicky

9aaTAD; Myc; MycN; KIX; CBP

Štítky

14110224, 14110518, CF BIC, CF NMR, CF PROT, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 25. 3. 2025 11:37, Mgr. Eva Dubská

Anotace

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.

Návaznosti

NV19-05-00410, projekt VaV

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

Investor: Ministerstvo zdravotnictví ČR, Úloha cytotoxických gamma-delta T buněk na terapeutické rezistenci a recidivě Glioblastoma Multiforme

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

KNIGHT, Andrea, Josef HOUSER, Tomáš OTAŠEVIČ, Vilém JURÁŇ, Václav VYBÍHAL, Martin SMRČKA a Martin PISKÁČEK. Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity. Molecular Medicine. New York: SPRINGER, 2024, roč. 30, č. 1, s. 1-9. ISSN 1076-1551. Dostupné z: 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 a Martin PISKÁČEK. Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity. \textit{Molecular Medicine}. New York: SPRINGER, 2024, roč.~30, č.~1, s.~1-9. ISSN~1076-1551. Dostupné z: https://dx.doi.org/10.1186/s10020-024-00896-7.

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