GENE-EXPRESSION AND CELL-CYCLE ARREST MEDIATED BY TRANSCRIPTION FACTOR DMP1 IS ANTAGONIZED BY D-TYPE CYCLINS THROUGH A CYCLIN-DEPENDENT-KINASE-INDEPENDENT MECHANISM

A novel 761-amino-acid transcription factor, DMP1, contains a central DNA binding domain that includes three imperfect myb repeats flanked b y acidic transactivating domains at the amino and carboxyl termini. D- type cyclins associate with a region of the DMP1 DNA binding domain im mediately adjacent to the myb repeats to form heteromeric complexes wh ich detectably interact neither with cyclin-dependent kinase 4 (CDK4) nor with DNA, The segment of D-type cyclins required for its interacti on with DMP1 falls outside the ''cyclin box,'' which contains the resi dues predicted to contact CDK4, Hence, D-type cyclin point mutants tha t do not interact with CDK4 can still bind to DMP1. Enforced coexpress ion of either of three D-type cyclins (D1, D2, or D3) with DMP1 in mam malian cells canceled its ability to activate gene expression. This pr operty was not shared by cyclins A, B, C, or H; did not depend upon CD K4 or CDK2 coexpression; was not subverted by a mutation in cyclin D1 that prevents its interaction with CDK4; and was unaffected by inhibit ors of CDK4 catalytic activity. Introduction of DMP1 into mouse NIH 3T 3 fibroblasts inhibited entry into S phase. Cell cycle arrest depended upon the ability of DMP1 to bind to DNA and to transactivate gene exp ression and was specifically antagonized by coexpression of D-type cyc lins, including a D1 point mutant that does not bind to CDK4. Taken to gether, these findings suggest that DMP1 induces genes that inhibit S phase entry and that D-type cyclins can override DMP1-mediated growth arrest in a CDK-independent manner.