MTBP and MYC: A Dynamic Duo in Proliferation, Cancer, and Aging

The oncogenic transcription factor c-MYC (MYC) is highly conserved across species and is frequently overexpressed or dysregulated in human cancers. MYC regulates a wide range of critical cellular and oncogenic activities including proliferation, metabolism, metastasis, apoptosis, and differentiation by transcriptionally activating or repressing the expression of a large number of genes. This activity of MYC is not carried out in isolation, instead relying on its association with a myriad of protein cofactors. We determined that MDM Two Binding Protein (MTBP) indirectly binds MYC and is a novel MYC transcriptional cofactor. MTBP promotes MYC-mediated transcriptional activity, proliferation, and cellular transformation by binding in a protein complex with MYC at MYC-bound promoters. This discovery provided critical context for data linking MTBP to aging as well as a rapidly expanding body of evidence demonstrating MTBP is overexpressed in many human malignancies, is often linked to poor patient outcomes, and is necessary for cancer cell survival. As such, MTBP represents a novel and potentially broad reaching oncologic drug target, particularly when MYC is dysregulated. Here we have reviewed the discovery of MTBP and the initial controversy with its function as well as its associations with proliferation, MYC, DNA replication, aging, and human cancer.