A novel factor distinct from E2F mediates C-MYC promoter activation through its E2F element during exit from quiescence

Abstract

Although C-MYC is overexpressed in a number of tumors, the mechanisms governing its expression in normal or tumor cells are not completely understood. Recruitment of the Retinoblastoma protein family members to gene promoters by E2F factors has a dominant negative effect on their activity during the G(0) and G(1) phases of the cell cycle. Despite the presence of an E2F-binding site on the C-MYC promoter, it escapes the repressive effect of E2F-Retinoblastoma complexes through unknown mechanisms during exit from quiescence. We hypothesized that occupancy of E2F elements by factors distinct from E2F might account for this escape. To test this hypothesis, we investigated whether the E2F element in the C-MYC promoter is regulated differently than E2F elements in promoters that are activated at the G(1)-S transition. Employing gel shift analysis, the E2F element from the C-MYC promoter was found to form a unique non-E2F complex, referred to as E2F C-MYC Specific (EMYCS), which is not observed with E2F elements from several other promoters. The DNA contact residues for EMYCS are distinct but overlapping with residues required for binding of E2F proteins. Finally, the approximate estimated molecular weight of the DNA-binding component of EMCYS is 105 kDa. Functional studies indicate that EMYCS has transcriptional transactivation capacity and suggest that it is required to activate the C-MYC promoter during exit from quiescence.

E2F4 plays a key role in Burkitt lymphoma tumorigenesis

“…Several groups, including ours, have described the formation of four major retarded complexes between E2F sites and nuclear extracts from several cell types, including LCL cell lines. 26,28,29 These complexes contained E2F associated to p107 and p130 (complex I), E2F bound to pRB (complex II), and either E2F4 (complex III) or E2F5 (complex IV) 'free' from association with pRB family members. 26,28,29 Accordingly, the interaction of nuclear extracts from various LCL cell lines and the labeled E2F1-d probe gave rise to four major retarded complexes (Figure 2a) whose formation was inhibited by an excess of the same unlabeled oligonucleotide (Figure 2b).…”

Myc and cell cycle control

“…On the other hand, Myc promoter contains an E2F site which is important for Myc expression [123,124]. However, the E2F site on Myc promoter does not seem to bind E2F proteins but a different transcription factor not yet identified [125]. Therefore, the precise mechanism of the Myc-E2F functional interaction awaits further study.…”

Perspectives in Cell Cycle Regulation: Lessons from an Anoxic Vertebrate

“…These pathways converge on the necessity of pRb2/p130 and CKIs [47, 48, 53, 54, 55]. The Rb family member pRb2/p130, recruits the repressive E2F-4 to E2F target promoters and facilitates binding to chromatin-remodeling complexes [54]. This chromatin remodeling blocks the transcription of many positive regulators of the cell cycle.…”