Ns. Liu et al., A NEW MODEL OF CELL-CYCLE-REGULATED TRANSCRIPTION - REPRESSION OF THECYCLIN-A PROMOTER BY CDF-1 AND ANTI-REPRESSION BY E2F, Oncogene, 16(23), 1998, pp. 2957-2963
Cell cycle regulation of the cyclin A gene is determined by a bipartit
e repressor binding site in the region of the basal promoter, termed C
DE-CHR, which also controls the expression of cell cycle genes upregul
ated in S or G(2) (such as cdc25C). The CDE-CHR in the cyclin A promot
er is recognized by both E2F complexes and CDF-1, but the contribution
of each of these factors in cell cycle regulation is unknown. In the
present study, we have introduced mutations into the cyclin A promoter
which lead to either a loss or enhancement of E2F binding, while havi
ng only marginal effects on the interaction with CDF-1. Unlike mutants
deficient for CDF-1 binding, promoter variants lacking E2F binding sh
owed an unchanged repression in G(0), thus identifying CDF-1 as the pr
incipal repressor of the cyclin A gene. The same mutants did show, how
ever, a delayed derepression while a mutation leading to increased E2F
binding resulted in premature up-regulation. These findings clearly s
uggest that E2F contributes to the correct timing of cyclin A transcri
ption, presumably by acting as an anti-repressor. In agreement with th
is conclusion, we find that the cyclin A promoter only poorly interact
s with E2F-4, which is the major E2F family member in G, cells, while
a clear binding is seen with E2F-1 and -3, which are up-regulated in l
ate G(1).