Induction of cyclin D1 gene transcription by estrogen receptor ␣ (ER␣) plays an important role in estrogenmediated proliferation. There is no classical estrogen response element in the cyclin D1 promoter, and induction by ER␣ has been mapped to an alternative response element, a cyclic AMP-response element at ؊57, with possible participation of an activating protein-1 site at ؊954. The action of ER␤ at the cyclin D1 promoter is unknown, although evidence suggests that ER␤ may inhibit the proliferative action of ER␣. We examined the response of cyclin D1 promoter constructs by luciferase assay and the response of the endogenous protein by Western blot in HeLa cells transiently expressing ER␣, ER␣K206A (a derivative that is superactive at alternative response elements), or ER␤. In each case, ER activation at the cyclin D1 promoter is mediated by both the cyclic AMP-response element and the activating protein-1 site, which play partly redundant roles. The activation by ER␤ occurs only with antiestrogens. Estrogens, which activate cyclin D1 gene expression with ER␣, inhibit expression with ER␤. Strikingly, the presence of ER␤ completely inhibits cyclin D1 gene activation by estrogen and ER␣ or even by estrogen and the superactive ER␣K206A. The observation of the opposing action and dominance of ER␤ over ER␣ in activation of cyclin D1 gene expression has implications for the postulated role of ER␤ as a modulator of the proliferative effects of estrogen.

The MLL gene, the closest human homologue to the Drosophila trithorax gene, undergoes chromosomal translocation with a large number of different partner genes in both acute lymphoid and acute myeloid leukemias. We have identified a new partner gene, EEN, fused to MLL in a case of acute myeloid leukemia. The gene is located on chromosome 19p13, where two other MLL partner genes, ENL and ELL͞ MEN have also been identified. The deduced protein of 368 aa contains a central ␣-helical region and a C-terminal Src homology 3 (SH3) domain most similar to the C-terminal SH3 domain found in the Grb2͞Sem-5͞Drk family of genes. Sequence analysis of the fusion MLL͞EEN transcript in our patient reveals that exon 6 of MLL is fused to the N-terminal end of EEN, a fusion that would create a chimeric protein that includes the major functional domain of EEN. EEN is expressed in a variety of tissue types and encodes a protein of approximately 46 kDa. The EEN protein is the human homologue of a member of a recently described murine SH3 domain-containing protein family. It is also highly related to a putative gene identified in Caenorhabditis elegans, and a number of similar sequences are present in the EST databases of several species.

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