E2F-dependent regulation of human MYC: trans-activation by cyclins D1 and A overrides tumour suppressor protein...

Transcription of the human proto-oncogene MYC is repressed in quiescent or non-dividing cells. Upon mitogenic stimulation expression of MYC is rapidly and transiently induced, maintained throughout G1, and declines to a basal level throughout further cell cycle transitions. Regulation of MYC promoter activity critically depends on the presence of a binding site for transcription factor E2F. Human E2F has been implicated also in the control of cell cycle progression through it association with the retinoblastoma suppressor gene product RB, and with multimeric protein complexes containing the G1-S- and S-phase cyclins E and A, respectively. Using CAT reporter co-transfection assays we show here that transcription from the MYC P2 promoter is induced efficiently by E2F-1, but repressed by RB. Furthermore, overexpression of cyclin A strongly activates the MYC promoter and this effect is further enhanced by coexpression of E2F-1 and cyclin A. We also find that expression of G1-phase cyclin D1 leads to an E2F binding site-dependent trans-activation of the MYC promoter and that this activation can be abrogated by overexpression of RB. The interaction of D-type G1 cyclins with RB resembles that of the adenovirus E1A protein with RB in that it can disrupt inhibitory E2F-RB complexes. Our results support a model in which intervention of distinct cyclins and their respective associated kinases promotes transcriptional activation of MYC throughout the cell cycle either by conversion of E2F within multimeric complexes into an active transcription factor or by liberation of free functional E2F.