EXPRESSION OF THE HSORC1 GENE, A HUMAN ORC1 HOMOLOG, IS REGULATED BY CELL-PROLIFERATION VIA THE E2F TRANSCRIPTION FACTOR

The initiation of DNA replication in Saccharomyces cerevisiae requires the action of a multisubunit complex of six proteins known as the ori gin recognition complex (ORC). The identification of higher eukaryotic homologs of several ORC components suggests a universal role for this complex in DNA replication. We now demonstrate that the expression of one of these homologs is regulated by cell proliferation, Expression of the human Orc1 gene (HsOrc1) is low in quiescent cells, and it is t hen dramatically induced upon stimulation of cell growth. In contrast, expression of the HsOrc2 gene does not appear to be similarly regulat ed, We have isolated the promoter that regulates HsOrc1 transcription, and we show that the promoter confers cell growth-dependent expressio n, We also demonstrate that the cell growth control is largely the con sequence of E2F-dependent negative transcription control in quiescent cells. Activation of HsOrc1 transcription following growth stimulation requires G(1) cyclin-dependent kinase activity, and forced E2F1 expre ssion can bypass this requirement, These results thus provide a direct link between the initiation of DNA replication and the cell growth re gulatory pathway involving G(1) cyclin-dependent kinases, the Rb tumor suppressor, and E2F.