Macrophages play an essential role in the resolution of tissue damage through removal of necrotic cells, thus paving the way for tissue regeneration. Macrophages also directly support the formation of new tissue to replace the injury, through their acquisition of an anti-inflammatory, or M2, phenotype, characterized by a gene expression program that includes IL-10, the IL-13 receptor, and arginase 1. We report that deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1, Il10, II13ra, and Arg-1 genes, whereas the inflammatory (M1) genes Il1, Il6, Tnfa, and Il12 are not affected. Mice carrying the mutated Cebpb promoter (␤⌬Cre) remove necrotic tissue from injured muscle, but exhibit severe defects in muscle fiber regeneration. Conditional deletion of the Cebpb gene in muscle cells does not affect regeneration, showing that the C/EBP␤ cascade leading to muscle repair is muscle-extrinsic. While ␤⌬Cre macrophages efficiently infiltrate injured muscle they fail to upregulate Cebpb, leading to decreased Arg-1 expression. CREB-mediated induction of Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration, providing a direct genetic link between these two processes.macrophage polarization ͉ muscle regeneration ͉ transcription

TEL is a gene frequently involved in specific chromosomal translocations in human leukemia and sarcoma that encodes a member of the ETS family of transcriptional regulators. TEL is unusual among other ETS proteins by its ability to self-associate in vivo, a property that is essential to the oncogenic activation of TEL-derived fusion proteins. We show here that TEL is a sequence-specific transcriptional repressor of ETS-binding site-driven transcription of model and natural promoters. Deletion of the oligomerization domain of TEL or its substitution by the homologous region of monomeric ETS1 impaired the ability of TEL to repress. In contrast, substitution of the oligomerization domain of TEL by unrelated oligomerization domains resulted in an active repressor, showing that the ability of TEL to repress depends on its ability to self-associate. The study of the properties of TEL fusions to the heterologous DNA binding domain of Gal4 identified two autonomous repression domains in TEL, distinct from its oligomerization domain, that are essential to the ability of TEL to repress ETS-binding site-containing promoters. These results have implications for the normal function of TEL, its relation to other ETS proteins, and its role in leukemogenesis.Genes of the ETS family encode transcriptional regulators that are essential for a variety of developmental processes and for the response of cells to extracellular stimuli (for review see Ref. 1).Specific ETS genes are frequently rearranged in human solid tumors and leukemias as the result of chromosomal translocations. TEL 1 (ETV6) is an ETS family member that was originally identified by virtue of its fusion to the 3Ј-half of the gene encoding the platelet-derived growth factor ␤ receptor in chronic myelomonocytic leukemia harboring a t(5;12)(q33;p13) chromosomal translocation (2). Other translocations in either leukemia or sarcoma also result in the fusion of TEL either to genes encoding other protein tyrosine kinases, including c-ABL (3, 4), JAK2 (5, 6), and TRKC (7) or to genes encoding known or alleged transcriptional regulators (8 -11).TEL is widely expressed throughout mouse embryonic development and in most human and mouse tissues and cell lines (12, 13). It is essential to mouse development as its inactivation by homologous recombination results in early lethality. Embryos show defects in yolk sac angiogenesis and in the survival of select mesenchymal and neural cells (13). TEL shares with other ETS proteins an evolutionarily conserved domain (ETS domain) that is responsible for its ability to bind consensus ETS-binding site (EBS) DNA elements (12). It also shares with a subset of other ETS proteins a conserved amino-terminal domain that is referred to as the B domain, the pointed domain, or the helix-loop-helix domain (2, 14). The recent elucidation of the structure of the B/pointed domain of ETS1 by NMR shows that this domain identifies a novel fold, unrelated to the helixloop-helix motif (15). Although its precise function is unknown, the B/pointed domain of s...

The transcriptional regulators that couple interfollicular basal keratinocyte proliferation arrest to commitment and differentiation are yet to be identified. Here we report that the basic region leucine zipper transcription factors C/EBPalpha and C/EBPbeta are co-expressed in basal keratinocytes, and are coordinately upregulated as keratinocytes exit the basal layer and undergo terminal differentiation. Mice lacking both C/EBPalpha and beta in the epidermis showed increased proliferation of basal keratinocytes and impaired commitment to differentiation. This led to ectopic expression of keratin 14 (K14) and DeltaNp63 in suprabasal cells, decreased expression of spinous and granular layer proteins, parakeratosis and defective epidermal water barrier function. Knock-in mutagenesis revealed that C/EBP-E2F interaction was required for control of interfollicular epidermis (IFE) keratinocyte proliferation, but not for induction of spinous and granular layer markers, whereas C/EBP DNA binding was required for DeltaNp63 downregulation and K1/K10 induction. Finally, loss of C/EBPalpha/beta induced stem cell gene expression signatures in the epidermis. C/EBPs, therefore, couple basal keratinocyte cell cycle exit to commitment to differentiation through E2F repression and DNA binding, respectively, and may act to restrict the epidermal stem cell compartment.

The TEL/ETV6 gene is located at 12p13 and is frequently involved in chromosomal translocations in human malignancies usually resulting in the expression of fusion proteins between the amino terminal part of TEL, and either unrelated transcription factors or protein tyrosine kinases. We report here a novel gene named TELB which is located on human chromosomal band 6p21 and encodes a protein highly related to TEL. TELB is widely expressed in dierent tissues and, similarly to TEL encodes a sequence-speci®c transcriptional repressor. Oncogene (2000) 19, 4802 ± 4806. Keywords: transcriptional repression; ETS; TELThe TEL (Translocated Ets Leukemia, also known as ETV6) gene (Golub et al., 1994), which encodes a member of the ETS family of transcription factors, is aected in more than half of the abnormalities of the short arm of the chromosome 12 in various hematopoietic malignancies, and in solid tumours.An intriguing characteristic of TEL-derived fusion oncoproteins is that the contribution of TEL appears variable and that the fusion partners are not functionally homogeneous but they fall in several dierent categories (for a recent review see Rubnitz et al., 1999). In the ®rst category, the amino-terminal domain of TEL is fused to the catalytic domain of several protein tyrosine kinases (PDGFRb, ABL, JAK2, NTRK3). In these examples, the TEL protein provides a speci®c domain which induces the selfassociation of the fusion proteins to constitutively activate their tyrosine kinase activity. In the second category, TEL drives the expression of unrelated transcription factors such as MDS1/EVI1 or CDX2, as a result of t(3;12)(q26;p13) and t(12;13)(p13;q12) chromosomal translocations, respectively. In a third category, exempli®ed by the t(12;22)(p13;q11) and t(4;12)(q11-q12;p13) chromosomal translocations, the transcription of the chimeric gene is driven by the partner chromosome and the fusion proteins contain the ETS DNA binding domain of TEL, indicating that the fusion protein could disregulate TEL target genes.The most frequent TEL fusion is the TEL ± AML1 fusion that results from the childhood B type ALL speci®c t(12;21)(p13;q22). The crucial fusion protein is TEL ± AML1 which contains the 336 aminoterminal residues of TEL, including its oligomerization and repressor domains, and almost all the AML1 protein.As a result, the fusion protein has been proposed to interfere with the normal transcriptional regulation of AML1 target genes. In virtually all cases, the t(12;21) is associated with loss of expression of the untranslocated TEL copy, usually due to total or partial deletion. Whether this is important for TEL ± AML1 malignant function proper or for the achievement of a loss of function for TEL is not established. Regarding this question, several examples have been reported in which translocations do not create fusion products but rather result in the impairment of TEL functions, which is regarded as an additional modality for TEL disregulation.Our understanding of TEL's involvement in leukemogenesis is expected to b...

Background: Extracellular signaling through receptors for neurotrophins mediates diverse neuronal functions, including survival, migration and differentiation in the central nervous system, but the transcriptional targets and regulators that mediate these diverse neurotrophin functions are not well understood.