Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1.
The cyclin D-dependent kinases CDK4 and CDK6 trigger phosphorylation of the retinoblastoma protein (RB) late in G1 phase, helping to cancel its growth-suppressive function and thereby facilitating S-phase entry. Although specific inhibition of cyclin D-dependent kinase activity in vivo can prevent cells from entering S phase, it does not affect S-phase entry in cells lacking functional RB, implying that RB may be the only substrate of CDK4 and CDK6 whose phosphorylation is necessary for G1 exit. Using a yeast two-hybrid interactive screen, we have now isolated a novel cyclin D-interacting myb-like protein (designated DMP1), which binds specifically to the nonamer DNA consensus sequences CCCG(G/T)ATGT to activate transcription. A subset of these DMP1 recognition sequences containing a GGA trinucleotide core can also function as Ets-responsive elements. DMP1 mRNA and protein are ubiquitously expressed throughout the cell cycle in mouse tissues and in representative cell lines. DMP1 binds to D-type cyclins directly in vitro and when coexpressed in insect Sf9 cells. In both settings, it can be phosphorylated by cyclin D-dependent kinases, suggesting that its transcriptional activity may normally be regulated through such mechanisms. These results raise the possibility that cyclin D-dependent kinases regulate gene expression in an RB independent manner, thereby serving to link other genetic programs to the cell cycle clock.
Hirai
H
H
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Sherr
C J
CJ
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D016384:Consensus Sequence; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D020598:Proto-Oncogene Proteins c-myb; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D017386:Sequence Homology, Amino Acid; D018411:Spodoptera; D015534:Trans-Activators / Q000737:chemistry; D014157:Transcription Factors / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection
D056741:Cyclin D; D016213:Cyclins; C491126:DMTF1 protein, human; C102116:Dmtf1 protein, mouse; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D014157:Transcription Factors; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases