TLR-induced innate immunity and inflammation are mediated by signaling cascades leading to activation of the MAPK family of Ser/Thr protein kinases, including p38 MAPK, which controls cytokine release during innate and adoptive immune responses. Failure to terminate such inflammatory reactions may lead to detrimental systemic effects, including septic shock and autoimmunity. In this study, we provide genetic evidence of a critical and nonredundant role of MAPK phosphatase (MKP)-1 in the negative control of MAPK-regulated inflammatory reactions in vivo. MKP-1−/− mice are hyperresponsive to low-dose LPS-induced toxicity and exhibit significantly increased serum TNF-α, IL-6, IL-12, MCP-1, IFN-γ, and IL-10 levels after systemic administration of LPS. Furthermore, absence of MKP-1 increases systemic levels of proinflammatory cytokines and exacerbates disease development in a mouse model of rheumatoid arthritis. When activated through TLR2, TLR3, TLR4, TLR5, and TLR9, bone marrow-derived MKP-1−/− macrophages exhibit increased cytokine production and elevated expression of the differentiation markers B7.2 (CD86) and CD40. MKP-1-deficient macrophages also show enhanced constitutive and TLR-induced activation of p38 MAPK. Based on these findings, we propose that MKP-1 is an essential component of the intracellular homeostasis that controls the threshold and magnitude of p38 MAPK activation in macrophages, and inflammatory conditions accentuate the significance of this regulatory function.

Schizophrenia is a common disorder with a life time prevalence of approximately 1 per cent. The illness often develops in young adults, who were previously normal, and is characterized by a constellation of symptoms including hallucinations and delusions (psychotic symptoms) and symptoms such as severely inappropriate emotional responses, a disorder of thinking and concentration, erratic behaviour as well as social and occupational deterioration. A considerable proportion of the variance in the liability to develop schizophrenia may be genetic, but segregation analysis, to establish a mode of transmission, has not produced a consistent result. One of these studies was carried out in Iceland and made use of the large family size and extensive geneaological information present in that country. Here we demonstrate genetic linkage of two DNA polymorphisms on the long arm of human chromosome 5 to schizophrenia in seven British and Icelandic families with multiple affected members. The results indicate the existence of a gene locus with a dominant schizophrenia-susceptibility allele. Inheritance of the allele in the families studied suggests that it may also predispose to psychiatric conditions such as schizophrenia spectrum disorders and a variety of other disorders. This report provides the first strong evidence for the involvement of a single gene in the causation of schizophrenia.

The Tel gene (or ETV6) is the target of the translocation (12;22)(p13;q11) in myeloid leukemia. TEL is a member of the ETS family of transcription factors and contains the pointed protein interaction (PNT) domain and an ETS DNA binding domain (DBD). By contrast to other chimeric proteins that contain TEL's PNT domain, such as TEL-platelet-derived growth factor ␤ receptor in t(5;12)(q33;p13), MN1-TEL contains the DBD of TEL. The N-terminal MN1 moiety is rich in proline residues and contains two polyglutamine stretches, suggesting that MN1-TEL may act as a deregulated transcription factor. We now show that MN1-TEL type I, unlike TEL and MN1, transforms NIH 3T3 cells. The transforming potential depends on both N-terminal MN1 sequences and a functional TEL DBD. Furthermore, we demonstrate that MN1 has transcription activity and that MN1-TEL acts as a chimeric transcription factor on the Moloney sarcoma virus long terminal repeat and a synthetic promoter containing TEL binding sites. The transactivating capacity of MN1-TEL depended on both the DBD of TEL and sequences in MN1. MN1-TEL contributes to leukemogenesis by a mechanism distinct from that of other chimeric proteins containing TEL.The Tel gene (or ETV6) encodes a member of the ETS family of transcription factors and is located on chromosome 12 band p13. Tel was discovered as part of a fusion gene created by a translocation (5;12) in a case of chronic myelomonocytic leukemia (20). Extensive analysis of other leukemia cases by fluorescent in situ hybridization analysis revealed that Tel is a frequent target of translocations. Over 30 different rearrangements involving Tel have been described, and over 10 of these have been cloned (45). Tel encodes two proteins, one starting at the first AUG (methionine 1) and one at the second AUG (methionine 43). Both isoforms contain an N-terminal pointed (PNT) domain involved in protein-protein interactions and a C-terminal ETS domain that binds DNA. In transient-transfection experiments, TEL appears to function as a transcriptional repressor by recruitment of histone deacetylases via the transcriptional corepressors mSin3A, SMRT,13,34). In addition, the central region of TEL also contains two autonomous repression domains (34), which depend on TEL self-association.In most cases, Tel translocations encode fusion proteins that contain the PNT domain fused to phosphotyrosine kinase (PTK) domains, such as those of platelet-derived growth factor ␤ receptor, ABL, JAK2, NTRK3, and ARG (7,12,20,21,26,29,40,41). In these fusion proteins, the PNT domain provides the oligomerization interface (24) needed for activation of the fused PTK moieties (5, 21, 47). The activated PTKs are directly responsible for the in vitro and in vivo transforming activities of these proteins (6,21,33,47,50). The PNT domain is also present in several fusions with transcription factors such as AML1, MDS1 (or EVI1), and CDX2 (9,19,41,44). It is unknown at present how addition of the PNT domain alters the functions of these transcription factors or how this wou...

TEL2/ETV7 is highly homologous to the ETS transcription factor TEL/ETV6, a frequent target of chromosome translocation in human leukemia. Although both proteins are transcriptional inhibitors binding similar DNA recognition sequences, they have opposite biologic effects: TEL inhibits proliferation while TEL2 promotes it. In addition, forced expression of TEL2 but not TEL blocks vitamin D3-induced differentiation of U937 and HL60 myeloid cells. TEL2 is expressed in the hematopoietic system, and its expression is up-regulated in bone marrow samples of some patients with leukemia, suggesting a role in oncogenesis. Recently we also showed that TEL2 cooperates with Myc in B lymphomagenesis in mice. Here we show that forced expression of TEL2 alone in mouse bone marrow causes a myeloproliferative disease with a long latency period but with high penetrance. This suggested that secondary mutations are necessary for disease development. Treating mice receiving transplants with TEL2-expressing bone marrow with the chemical carcinogen Nethyl-N-nitrosourea (ENU) resulted in significantly accelerated disease onset. Although the mice developed a GFP-positive myeloid disease with 30% of the mice showing elevated white blood counts, they all died of T-cell lymphoma, which was GFP negative. Together our data identify TEL2 as a bona fide oncogene, but leukemic transformation is dependent on secondary mutations. IntroductionThe ETS (E26 transformation specific) proteins belong to a large family of eukaryotic transcription factors (TFs) unique to the metazoan lineage and highly conserved throughout evolution. 1,2 Some ETS proteins are expressed ubiquitously while others show a restricted tissue distribution. 3,4 All ETS proteins possess a highly conserved 85-amino acid (aa) ETS domain that binds a purine-rich GGAA/T core motif present in promoters and enhancers of different target genes. 4,5 A subgroup of ETS TFs, including the TEL proteins, also contains a conserved pointed (PNT) protein-protein interaction domain, which mediates the formation of homodimers/ oligomers 6,7 and heterodimers/oligomers. 8,9 In TEL this domain is involved in transcriptional repression. 10 Vertebrate ETS TFs are implicated in many aspects of normal development and differentiation, including that of the hematopoietic system. 11 For example, Ets-1, Fli-1, and Erg are expressed early during mouse development in the blood islands of the yolk sac where hemangioblasts are present. 12 A high level of Pu-1 expression in CD34 ϩ hematopoietic progenitors directs their differentiation toward the macrophage lineage, while low Pu-1 expression induces B-cell differentiation. 13 The expression of IL-7R␣, a receptor essential for pro-B-cell development, is directly regulated by Pu-1 in lymphoid progenitors. 3,14 The ubiquitously expressed TEL/ETV6 is essential for normal embryonic yolk sac angiogenesis and is important for the maintenance of the adult bone marrow microenvironment. 15 Several ETS genes, including ETS1, ETS2, PU1, FLI1, TEL/ ETV6, and ERG, possess oncog...