Myc proto-oncogene protein transactivation domain (MYC TAD)

The Myc proto-oncogene protein transactivation domain (MYC TAD) is an intrinsically disordered region located at the N-terminus (residues 1–143) of the MYC protein, a master regulator of cellular processes [UniProt, 2024]. It contains highly conserved motifs known as Myc Boxes (MB0, MBI, MBII, and MBIIIb) that function as essential scaffolds for recruiting transcriptional co-activators [Nature Reviews Cancer, 2022]. These co-activators include the TRRAP-containing histone acetyltransferase complexes and the Mediator complex, which are vital for MYC-mediated gene activation [Cell, 2017]. This transcriptional activity drives critical cellular processes such as cell cycle progression, metabolic reprogramming, and biomass accumulation [PubMed, 2021]. In many human malignancies, the MYC TAD is a focal point for oncogenic activity, often being stabilized by phosphorylation or overexpressed due to gene amplification [Oncogene, 2018]. Although the TAD's lack of a stable tertiary structure has historically made it a difficult target for small-molecule drug discovery, it remains a high-priority therapeutic target in oncology [Journal of Medicinal Chemistry, 2023]. Current strategies include the development of peptidomimetics and small molecules designed to disrupt specific protein-protein interactions, such as the MYC-TRRAP or MYC-CBP/p300 interfaces [Trends in Pharmacological Sciences, 2020]. These approaches aim to selectively inhibit MYC's transcriptional output and induce apoptosis in MYC-dependent cancer cells [Cancer Cell, 2019].

Other names

c-Myc transactivation domainMYC N-terminal domainMyc Box I and II domainMYC TAD

Inhibition of transcriptional co-activator recruitment by disrupting protein-protein interactions at the Myc Boxes (MBI, MBII) within the transactivation domain [Nature Reviews Cancer, 2022].