MYC Degradation

Abstract

The MYC oncoprotein is an essential transcription factor that regulates the expression of many genes involved in cell growth, proliferation, and metabolic pathways. Thus, it is important to keep MYC activity in check in normal cells in order to avoid unwanted oncogenic changes. Normal cells have adapted several ways to control MYC levels, and these mechanisms can be disrupted in cancer cells. One of the major ways in which MYC levels are controlled in cells is through targeted degradation by the ubiquitin-proteasome system (UPS). Here, we discuss the role of the UPS in the regulation of MYC protein levels and review some of the many proteins that have been shown to regulate MYC protein stability. In addition, we discuss how this relates to MYC transcriptional activity, human cancers, and therapeutic targeting.

WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

“…ÃÃ , P < 0.01; ÃÃÃ , P < 0.001. to transcriptional activation (40)(41)(42). In this study, we have identified both canonical and noncanonical E-Boxes at the WDR5 gene core promoter, and confirmed that N-Myc directly binds to the WDR5 gene core promoter and upregulates WDR5 mRNA and protein expression in neuroblastoma cells.…”

An Overview of MYC and Its Interactome

“…However, the exact half-lives of MYC family proteins are dependent on physiological context, and, in many tumors, stabilization of MYC contributes to its deregulation (Salghetti et al 1999;Gregory and Hann 2000;Sears et al 2000;Cartwright et al 2005). Multiple ubiquitin ligases have recently been shown to control MYC stability (see Farrell and Sears 2014). One of these ubiquitin ligases, FBW7, regulates MYC and MYCN stability in response to phosphorylation of Serine 62 and Threonine 58 within MBI (Welcker et al 2004a,b;Yada et al 2004).…”

The Role of MIZ-1 in MYC-Dependent Tumorigenesis

“…This may be either caused by the sequestration described above or simply because of steric masking of carboxy-terminal ubiquitination sites in MYC. Notably, ubiquitination of MYC and proteasomal turnover are critical for transcriptional activation by MYC (Kim et al 2003;von der Lehr et al 2003;Adhikary et al 2005;Farrell and Sears 2014). It is possible, therefore, that inhibition of ubiquitination of MYC by MIZ-1 is critical for blocking its transactivation function.…”