Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.

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AML1 (also called PEBP2␣B, CBFA2, or CBF␣2) is one of the most frequently disrupted genes in chromosome abnormalities seen in human leukemias. It has been reported that AML1 plays several pivotal roles in myeloid hematopoietic differentiation and other biological phenomena, probably through the transcriptional regulation of various relevant genes. Here, we investigated the mechanism of regulation of AML1 functions through signal transduction pathways. The results showed that AML1 is phosphorylated in vivo on two serine residues within the proline-, serine-, and threonine-rich region, with dependence on the activation of extracellular signal-regulated kinase (ERK) and with interleukin-3 stimulation in a hematopoietic cell line. These in vivo phosphorylation sites of AML1 were phosphorylated directly in vitro by ERK. Although differences between wild-type AML1 and phosphorylation site mutants in DNA-binding affinity were not observed, we have shown that ERK-dependent phosphorylation potentiates the transactivation ability of AML1. Furthermore the phosphorylation site mutations reduced the transforming capacity of AML1 in fibroblast cells. These data indicate that AML1 functions are potentially regulated by ERK, which is activated by cytokine and growth factor stimuli. This study provides some important clues for clarifying unidentified facets of the regulatory mechanism of AML1 function.The AML1 gene was first identified on chromosome 21 as the gene that is disrupted in the (8;21)(q22;q22) translocation (56, 66), which is one of the most frequent chromosome abnormalities associated with human acute myelogenous leukemia. In t(8;21)(q22;q22), the gene rearrangement results in the production of an AML1/MTG8(ETO) fusion protein (19,20,54). We and another group previously reported that the AML1 gene is also disrupted in t(3;21)(q26;q22), which is found in the blastic crisis phase of chronic myelogenous leukemia and therapy-related acute myelogenous leukemia (53,(59)(60)(61)(62). Recently, it was reported that the AML1 gene is rearranged in acute lymphoblastic leukemia carrying t(12;21) (p12;q22) (24, 77). On the other hand, PEBP2␣B (also called CBFA2 or CBF␣2), a mouse homolog of AML1, was first identified as the gene encoding a member of the polyomavirus enhancer-binding protein (PEBP) 2␣ family or the core-binding factor (CBF) ␣ (or A) family of the Moloney leukemia virus enhancer (6, 94). PEBP2 is a heterodimer composed of PEBP2␣ and PEBP2␤ (also called CBFB or CBF␤) (63, 95). Human PEBP2␤ is known to be disrupted in the inv(16)(p13q22) chromosome abnormality associated with acute myelogenous leukemia (46, 47).These findings suggest that the structural alteration of AML1 triggers the leukemic transformation and that intact AML1 may play important roles in hematopoietic cell differentiation and proliferation. We have shown that AML1 regulates myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms, suggesting that a transactivation property of AML1 is necessary fo...

Summary Epidemiological studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs), known to inhibit cyclooxygenase (COX), reduce the risk of colorectal cancer. COX is a key enzyme in prostaglandin biosynthesis, and two isoforms of COX, COX-1 and COX-2, have been identified. Recently COX-2 has been reported to frequently overexpress in colorectal neoplasms and to play a role in colorectal tumorigenesis and tumour progression. In this study, using immunohistochemistry, we examined COX-2 expression in advanced human colorectal cancer and its correlation with clinicopathological features. COX-2 expression was observed mainly in the cytoplasm of cancer cells in all the specimens examined, but some stromal cells and endothelial cells were also stained. According to the grade of COX-2 expression of the cancer cells, patients were divided into high-and low-COX-2 expression groups. High-COX-2 expression significantly correlated with tumour recurrence, especially haematogenous metastasis. These results suggest that a selective COX-2 inhibitor can be a novel class of therapeutic agents not only for tumorigenesis but also for haematogenous metastasis of cololectal cancer. To our knowledge, this is the first report on the correlation between COX-2 overexpression and recurrence of colorectal cancer.

The chromosomal translocation t(3;21)(q26;q22), which is found in blastic crisis in chronic myelogenous leukemias and myelodysplastic syndrome-derived leukemias, produces AML1/Evi-1 chimeric transcription factor and is thought to play important roles in acute leukemic transformation of hemopoietic stem cells. We report here the functional analyses of AML1/Evi-1. It was revealed that AML1/Evi-1 itself does not alter the transactivation level through mouse polyomavirus enhancer-binding protein 2 (PEBP2; PEA2) sites (binding site of AML1) but dominantly suppresses the transactivation by intact AML1, which is assumed to be a stimulator of myeloid cell differentiation. DNA-binding competition is a putative mechanism of such dominant negative effects of AML1/Evi-1 because it binds to PEBP2 sites with higher affinity than AML1 does. Furthermore, AML1/Evi-1 stimulated c-fos promoter transactivation and increased AP-1 activity, as Evi-1 (which is not normally expressed in hemopoietic cells) did. Experiments using deletion mutants of AML1/Evi-1 showed that these two functions are mutually independent because the dominant negative effects on intact AML1 and the stimulation of AP-1 activity are dependent on the runt domain (DNA-binding domain of AML1) and the zinc finger domain near the C terminus, respectively. Furthermore, we showed that AML1/Evi-1 blocks granulocytic differentiation, otherwise induced by granulocyte colony-stimulating factor, of 32Dcl3 myeloid cells. It was also suggested that both AML1-derived and Evi-1-derived portions of the fusion protein play crucial roles in this differentiation block. We conclude that the leukemic cell transformation in t(3;21) leukemias is probably caused by these dual functions of AML1/Evi-1 chimeric protein.Defined karyotypic abnormalities are observed in some types of human leukemias. By these chromosomal abnormalities, various genes encoding transcription factors are rearranged and the resultant fused genes produce chimeric proteins (9, 48). It is well known that the reciprocal translocations t(15;17)(q21;q21), t(8;21)(q22;q22), t(6;9)(p23;q34), and t(1; 19)(q23;q13.3) result in formation of chimeric transcription factor proteins PML/retinoic acid receptor ␣ chain (RAR␣) (12, 26), AML1/MTG8 (ETO) (15,39,41), DEK/CAN (68), and E2A/PBX1 (27, 49), respectively. Because these chimeric proteins should play causative roles in leukemogenesis, it is important to investigate both their transcriptional activities and their biological functions.The t(3;21)(q26;q22) translocation, seen in the blastic crisis phase of chronic myelogenous leukemia and myelodysplastic syndrome-derived leukemia, is thought to cause leukemic cell transformation of hemopoietic stem cells (56, 61). We and others recently reported that t(3;21)(q26;q22) fuses AML1 and Evi-1 (ecotropic viral integration site 1) genes and produces AML1/Evi-1 chimeric protein (38, 50) (Fig.