Identification of a region which directs the monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1).

Abstract

The receptor for the macrophage colony-stimulating factor (or colony-stimulating factor 1 ) is expressed from different promoters in monocytic cells and placental trophoblasts. We have demonstrated that the monocyte-specific expression of the CSF-1 receptor is regulated at the level of transcription by a tissue-specific promoter whose activity is stimulated by the monocyte/B-cell-specific transcription factor PU.1 (D.-E. Zhang, C. J. Hetherington, H.-M. Chen, and D. G. Tenen, Mol. Cell. Biol. 14:373-381, 1994). Here we report that the tissue specificity of this promoter is also mediated by sequences in a region II (bp -88 to -59), which lies 10 bp upstream from the PU.1-binding site. When analyzed by DNase footprinting, region II was protected preferentially in monocytic cells. Electrophoretic mobility shift assays confirmed that region II interacts specifically with nuclear proteins from monocytic cells. Two gel shift complexes (Mono A and Mono B) were formed with separate sequence elements within this region. Competition and supershift experiments indicate that Mono B contains a member of the polyomavirus enhancer-binding protein 2/core-binding factor (PEBP2/CBF) family, which includes the AML1 gene product, while Mono A is a distinct complex preferentially expressed in monocytic cells. Promoter constructs with mutations in these sequence elements were no longer expressed specifically in monocytes. Furthermore, multimerized region II sequence elements enhanced the activity of a heterologous thymidine kinase promoter in monocytic cells but not other cell types tested. These results indicate that the monocyte/B-cell-specific transcription factor PU.1 and the Mono A and Mono B protein complexes act in concert to regulate monocyte-specific transcription of the CSF-1 receptor.

True

“…Lineage-restricted genes activated include those encoding IL-3, T cell receptor subunits, GM-CSF, myeloperoxidase, neutrophil elastase, and the M-CSF receptor. 4,[18][19][20][21][22][23] In isolation, one to four CBF-binding sites increases the activity of the thymidine kinase promoter only three-fold in myeloid cells, indicating that CBF has weak intrinsic trans-activation potential. 18 However, CBF contributes potently to trans-activation in cooperation with Ets-1, PU.1, c-Myb or C/EBP␣.…”

Transcriptional regulation of osteopontin gene in vivo by PEBP2αA/CBFA1 and ETS1 in the skeletal tissues

“…This domain mediates DNA binding as well as dimerization to PEBP2b/CBFB, which has no direct DNA binding ability, and confers enhanced DNA binding capacity to PEBP2a (Ogawa et al, 1993b;Wang et al, 1993). PEBP2a speci®cally recognizes a consensus sequence, PuACCPuCA and has been reported to control polyoma virus enhancer (Kamachi et al, 1990), murine leukemia virus enhancers , T cell-speci®c genes (Giese et al, 1995;Hallberg et al, 1992;Hsiang et al, 1993;Prosser et al, 1992;Redondo et al, 1992), enzymes (myeloperoxidase, neutrophil elastase, granzyme B serine protease) (Nuchprayoon et al, 1994;Wargnier et al, 1995) and cytokines and their receptors (GM-CSF, IL3, CSF-1) (Cameron et al, 1994;Frank et al, 1995;Zhang et al, 1994). PEBP2aA and ETS1 have been shown to bind together and interact synergistically on the promoter of the T cell receptor a gene (Giese et al, 1995) and T cell receptor b gene (Wotton et al, 1994).…”

CBFβ-SMMHC, expressed in M4Eo AML, reduced CBF DNA-binding and inhibited the G1 to S cell cycle transition at the restriction point in myeloid and lymphoid cells

“…CBFs regulate both lymphoid and myeloid genes, including those encoding TCRd, IL-3, myeloperoxidase (MPO), neutrophil elastase, and the M-CSF Receptor (Redondo et al, 1992;Cameron et al, 1994;Suzow and Friedman, 1993;Nuchprayoon et al, 1994;Zhang et al, 1994).…”