PEBP2 alpha B/mouse AML1 consists of multiple isoforms that possess differential transactivation potentials.

Abstract

A murine transcription factor, PEBP2, is composed of two subunits, a and ,B. There are two genes in the mouse genome, PEBP2aA and PEBP2&aB, which encode the at subunit. Two types of the aLB cDNA clones, aLBi and aB2, were isolated from mouse fibroblasts and characterized. They were found to represent 3.8-and 7.9-kb transcripts, respectively. The 3.8-kb RNA encodes the previously described aB protein referred to as oiBl, while the 7.9-kb RNA encodes a 387-amino-acid protein, termed aB2, which is identical to aBl except that it has an internal deletion of 64 amino acid residues. Both otBl and aB2 associate with PEBP2,I and form a heterodimer. The atB2/4 complex binds to the PEBP2 binding site two-to threefold more strongly than the aB1/,I complex does. aBl stimulates transcription through the PEBP2 site about 40-fold, while aB2 is only about 25 to 45% as active as aBl. Transactivation domain is located downstream of the 128-amino-acid runt homology region, referred to as the Runt domain. Mouse chromosome mapping studies revealed that aA, aB, and ,B genes are mapped to chromosomes 17, 16, and 8, respectively. The last two genes are syntenic with the human AMLI on chromosome 21q22 and PEBP24/CBFD on 16q22 detected at the breakpoints of characteristic chromosome translocations of the two different subtypes of acute myeloid leukemia. These results suggest that the previously described chimeric gene products, AML1/MTG8(ETO) and AMLl-EAP generated by t(8;21) and t(3;21), respectively, lack the transactivation domain of AMLL.A murine transcription factor, PEBP2, also called PEA2, was identified as a factor which binds to the region of the polyomavirus enhancer originally termed the PEA2 site (35). PEBP2 functionally cooperates with other enhancer corebinding proteins, including AP1 and Ets family proteins, PEA3 (48), , and PEBP5 (2), and plays an important role in stimulation of transcription and viral DNA replication. PEBP2 is composed of a and 3 subunits (32, 34). The at subunit bind to DNA by recognizing the consensus sequence, (Pu/T) ACCPuCA (13,34). The companion 3 subunit binds to the cx protein and increases the affinity of the a protein to DNA without binding to DNA by itself (32). cDNAs coding for both subunits have been cloned and characterized in detail (32, 34).PEBP2 has recently been shown to be closely related to acute myeloid leukemia (AML). The t(8;21)(q22;q22) translocation is one of the most frequent chromosome abnormalities in AML and is classified into the FAB-M2 subtype of AML (39). It has been shown that the t(8;21) breakpoints in the chromosome 21 are clustered in the recently described AMLI gene (27), the product of which shares a high homology within the 128-amino-acid (aa) region with the product of the Drosophila segmentation gene, runt (14), and the at subunit of PEBP2 (8,9,34 genome, oaB, which shares a high sequence homology with the original ao gene, termed aA. The aB gene as a whole is highly homologous to human AMLl (3). The discovery of the homology of the AML1 protein to the otsubunit o...

The cDNA cloning of the transcripts of human PEBP2αA/CBFA1 mapped to 6p12.3-p21.1, the locus for cleidocranial dysplasia

“…Previously, we mapped mouse PEBP2aA (pebpa2a) to the central region of chromosome 17, 8.7 centimorgans (cM) distal to H-2 and 9.5 cM proximal to Vav. This locus was synthenic to human 6p, 19p or 5q (Bae et al, 1994). We now know that human PEBP2aA maps to 6p12.3-p21.1.…”

“…We showed earlier that the mouse PEBP2aA (pebpa2a, see Bae et al, 1994) locus was mapped to the central region of mouse chromosome 17 which is synthenic to human 6p, 19p or 5q (Bae et al, 1994). More recently, Levanon et al reported that human counterpart of PEBP2aA, which they termed AML3, was mapped to human chromosome 6p21.…”

“…The b subunit associates well with all three a subunits (Ogawa et al, 1993b;Bae et al, 1994Bae et al, , 1995. This means that structural alterations of any one of the a or b subunit genes would have potential to a ect the regulatory role of others.…”

“…There are three mammalian genes which encode the a subunit. They are PEBP2aA (Ogawa et al, 1993b), AML1/PEBP2aB (Bae et al, 1993(Bae et al, , 1994 and PEBP2aC (Bae et al, 1995;Levanon et al, 1994;Wijimenga et al, 1995). The a subunit contains the evolutionarily conserved 128 amino acid region termed the Runt domain responsible for the DNA binding and the heterodimerization activities .…”

“…The gene has been mapped to the central region of mouse chromosome 17. This locus is homologous to human chromosome 6p, 19p or 5q (Bae et al, 1994). This paper describes the cDNA sequence of human PEBP2aA.…”