Identification of novel targets of MYC whose transcription requires the essential MbII domain.

The MYC oncoprotein is among the most potent regulators of cell cycle progression and malignant transformation in human cells. Current models suggest that much of MYC's role in these processes is related to its ability to regulate the transcription of downstream target genes that encode the ultimate effector proteins. In addition to its carboxy-terminal DNA binding and dimerization domains, an enigmatic motif in the amino terminus termed MbII is required for all of MYC's biological activities. In spite of historical observations demonstrating the absolute requirement for MbII in these biological functions, clues implicating this domain in target gene transcription have only recently appeared. Based on this emerging link between MbII and transcriptional activation, we hypothesized that the identification of individual MYC targets whose transactivation requires MbII would help define the essential downstream effectors of MYC in transformation and cell cycle progression. In hopes of directly identifying new MbII-dependent MYC target genes, an expression profiling screen was conducted. This screen resulted in our identification of ten novel downstream targets of MYC. As a proof of principle, we recently demonstrated using RNAi-mediated depletion that one of these targets, the metastasis regulator MTA1, is absolutely required for MYC mediated transformation. Here we report the identity of these previously uncharacterized MYC targets and discuss their potential roles in MYC function. In addition, we attempt to reconcile the historical and contemporary evidence linking MbII to transcriptional activation.