We have identified and further characterized a Caenorhabditis elegans gene, CEZF, that encodes a protein with substantial homology to the zinc rmger and leucine zipper motifs of the human gene products AF10, MLLT6, and BR140. The first part of the zinc finger region of CEZF has strong similarity to the corresponding regions of AF10 (66%) and MLLT6 (64%) at the cDNA level. As this region is structurally different from previously described zinc finger motifs, sequence homology searches were done. Twenty-five other proteins with a similar motif were identified. Because the functional domain of this motif is potentially disrupted in leukemia-associated chromosomal translocations, we propose the name of leukemia-associated protein (LAP) finger. On the basis of these comparisons, the LAP domain consensus sequence is Cys'-Xaal-2-Cys2-Xaa,_21-Cys3-Xaa2-4-Cys4-Xaa4_5-His5-Xaa2-Cys6-Xaa2_46_-Cys7-Xaa2-Cys8, where subscripted numbers represent the number of amino acid residues. We review the evidence that this motif binds zinc, is the important DNA-binding domain in this group of regulatory proteins, and may be involved in leukemogenesis.The predicted product of the gene AFJO on. chromosome 10p12, involved in the translocation t(10;11)(pl2;q23) seen in acute myeloid leukemias (1), has a potential zinc finger domain at the N terminus and a leucine zipper near the C-terminal end. Homology exists at the protein level in the zinc finger and leucine zipper regions of AF10 with two previously described human DNA sequences: an MLL partner gene MLLT6 on chromosome 17q21 (2) and BR140 for which function and chromosomal location are unknown (3), and a putative Caenorhabditis elegans gene that we have named CEZF (1).t Although the zinc finger domains are conserved in these four genes, they do not show characteristics common to any of the previously described zinc-binding motifs described so far. There are at least six different families of cysteine-rich proteins identified to have zinc-binding domains (4). Of these the RING (5), LIM (6), and Kruppel (7) fingers have been involved in chromosomal translocations in acute leukemia. In this paper we further characterize CEZF and the conserved zinc finger domain. We report the identification of another class of zinc finger proteins involved in a wide range of proteins, including leukemia-associated fusion proteins. MATERIALS AND METHODSNucleic Acid Analysis. The partially sequenced C. elegans cDNA clone yK46c2 has been reported (1) to have homology with AF10. It is 3.2 kb in size, obtained from an oligo(dT)-primed A ZAP (Stratagene) C. elegans cDNA library, and maps to chromosome III (8). Complete sequencing of clone yK46c2 on both strands was done in an Applied Biosystem automatic sequencer using the Prism ready reaction dideoxy termination cycle sequencing kit (Applied Biosystems).DNA Alignment. Exon-intron boundaries were mapped by comparing the cDNA sequence with the C. elegans genomic sequence from cosmid F54F2.2 available in the data base (accession no. L23645) (8).Multiple P...

IntroductionHuman CD38 is the prototype of a family of proteins that share structural similarities and ectoenzymatic activities involved in the production of calcium-mobilizing compounds. [1][2][3] Aside from its ectoenzymatic activities and, apparently with independent modalities, CD38 may perform as a receptor, ruling adhesion and signaling in T 4 and B lymphocytes, 5 monocytes, 6 and natural killer (NK) cells. 7,8 The receptor functions of CD38 are regulated through interaction with a counterreceptor, identified as CD31. 9 The signaling events initiated by interactions between CD38 and CD31 (and fully mimicked by agonistic anti-CD38 monoclonal antibodies [mAbs]) were initially studied in the dynamic context of circulating CD38 ϩ T lymphocytes adhering to CD31 ϩ endothelial cells. 10 Use of this model allowed definition of some of the events that take place after the interaction and that include calcium (Ca ϩϩ ) mobilization from cytosolic stores, tyrosine phosphorylation of selected substrates, activation of nuclear factors, and secretion of cytokines. 11 It is generally agreed that CD38 controls a specific signaling pathway in T cells, B cells, NK cells, and monocytes. In spite of this evidence, the modalities through which the signal is initiated remain elusive. The molecule has neither the canonical structure of a receptor nor the hallmark domains. Indeed, the cytoplasmic tail is short and lacks docking sites and it is not tyrosine phosphorylated on activation. 12,13 Such negative characteristics are even more evident in CD157, the other member of the protein family, whose signaling features are known, notwithstanding a glycophosphatidylinositol linkage to the cell membrane. 14,15 Some clues can be extrapolated from cocapping experiments, which show that CD38 associates on the cell membrane with professional signaling receptors such as the T-cell receptor (TCR)-CD3 complex in T cells, the B-cell receptor (BCR) in B cells, and CD16 in NK cells. 16 A hypothesis to explain the signaling properties of CD38 is that the molecule exploits the signaling machinery of professional receptors to deliver its own independent signals. This idea was first supported by experiments using CD38 ϩ T-cell lines deficient in components of the signaling apparatus of the TCR-CD3 complex. 17,18 The inability of CD38 to signal in these cells was overcome by reconstituting a complete TCR-CD3 complex, thereby indicating that CD38 signaling depends on the presence of a functional TCR. These observations were recently expanded by studies using T lymphocytes purified from the intestinal The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From lamina propria as a model in which the TCR complex is physiologically impaired. 19 A comparative analysis of circulating versus residential T lymphocytes from the s...

A novel class of conserved transcription factors has been identified from the molecular cloning of AF10, the gene involved in the t(10;11)(p12;q23) translocation of acute myeloid leukemias. AF10 encodes a 109-kD protein of 1,027 amino acids and contains an N- terminal zinc finger region and a C-terminal leucine zipper. These structures have been found to be conserved in sequence and position in three other proteins, AF17, BR140, and a previously unrecognized Caenorhabditis elegans gene, provisionally named CEZF. The overall structure, level of sequence conservation, and expression pattern suggest that these genes encode a new class of transcription factors, some of which are targets for chromosomal translocation in acute leukemia.

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