Interactions Between MYC and BRD4 Result in Their Reciprocal Regulation

Division Of Basic Sciences - Nci

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Abstract

MYC is a critical regulator of proliferation and cell growth that broadly affects cell physiology through its interaction with over 300 cellular proteins 12. Among the proteins with which MYC interacts are those involved in chromatin structure, DNA damage repair, mitosis, ribosome biogenesis, RNA processing and transcription. Reflecting its broad role in cellular processes, homeostatic levels of MYC are tightly controlled. This control occurs at multiple points of MYC protein biogenesis: transcription, mRNA levels and half-life, and post-translationally through regulation of MYC turnover. Despite the large number of proteins with which MYC is known to interact, only a handful are known to affect its stability. Among those, kinases such as ERK1 and CDK2, phosphorylate MYC at Ser62, which is associated with stabilization. Until now, GSK3beta was the only kinase known to phosphorylate MYC at Thr5842, leading to its ubiquitination and degradation19. However, the cytoplasmic GSK3beta only translocates to the nucleus in response to extracellular signaling43 and thus is unlikely to contribute to homeostatic regulation of MYC. We have now discovered that the bromodomain protein, BRD4, is a second kinase that binds to MYC and phosphorylates at Thr58, leading to its ubiquitination and degradation. Unlike GSK3beta, BRD4 is constitutively nuclear and contributes to maintaining homeostatic levels of MYC. Furthermore, we have found that BRD4 also directly interacts with ERK1, forming a trimeric complex with ERK1 and MYC. Taken together, these results identify a regulatory network that maintains homeostatic levels of MYC protein through regulation of its stability.