Regulation of the CD13/aminopeptidase N gene by DMP1, a transcription factor antagonized by D-type cyclins.
The binding of the Myb-like DMP1 transcription factor to DNA consensus sequences [CCCG(G/T)ATGT] in artificial promoters is antagonized by D-type cyclins with no requirement for their catalytic partners, cyclin-dependent kinase (CDK) 4 and CDK6. The subset of DMP1 binding sites containing the GGA core can bind Ets family transcription factors Ets-1 and Ets-2. Screening of a series of natural promoters revealed that the CD13/aminopeptidase N (APN; EC 3.4.11.2) promoter could bind and be activated by DMP1. Activation of CD13/APN required both the intact DNA binding and transactivation domains of DMP1 and was inhibited by D-type cyclins, but not by cyclins A, B, C, or H, in a CDK-independent manner. CD13/APN is transactivated by a cooperative interaction between c-Myb bound to its cognate site and Ets-1 tethered to one of three GGA core-containing sites located 30-50 base pairs downstream. DMP1 binds to one of the Ets binding sites (designated Ets C) and synergizes with c-Myb in activating CD13/APN expression. Analysis of nuclear lysates from KG1a early myeloid cells using an oligonucleotide probe containing only the DMP1/Ets C binding site indicated that endogenous DMP1 and a putative Ets family member bind this element in vivo. DMP1-DNA complexes were significantly more stable than those containing the Ets factor. These data indicate that two different Myb family proteins collaborate in regulating APN gene expression and point to a role for DMP1 in normal myeloid cell development.
Inoue
K
K
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Sherr
C J
CJ
Shapiro
L H
LH
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D018826:CD13 Antigens / Q000235:genetics*; D056741:Cyclin D; D016213:Cyclins / Q000502:physiology*; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*
D056741:Cyclin D; D016213:Cyclins; D017931:DNA Primers; C102116:Dmtf1 protein, mouse; D014157:Transcription Factors; D018826:CD13 Antigens