Because androgen function is regulated by its receptors, androgen-androgen receptor signaling is crucial for regulating spermatogenesis. Androgen is mainly testosterone secreted by testis. Based on the results of early studies in goats, the administration of melatonin over an extended period of time increases steroid production, but the underlying mechanism remains unclear. Here, we report the expression of the melatonin membrane receptors MT1 and MT2 and the retinoic acid receptor-related orphan receptor-alpha (RORα) in the goat testis. An in vitro differentiation system using spermatogonial stem cells (SSCs) cultured in the presence of testicular somatic cells was able to support the formation of sperm-like cells with a single flagellum. The addition of 10-7 M melatonin to the in vitro culture system increased RORα expression and considerably improved the efficiency of haploid cell differentiation, and the addition of the RORα agonist CGP52608 significantly increased the testosterone concentration and expression of GATA binding factor 4 (GATA-4). Furthermore, inhibitors of melatonin membrane receptors and a RORα antagonist (T0901317) also led to a considerable reduction in the efficiency of haploid spermatid formation, which was coupled with the suppression of GATA-4 expression. Based on these results, RORα may play a crucial role in enhancing melatonin-regulated GATA-4 transcription and steroid hormone synthesis in the goat spermatogonial stem cell differentiation culture system.
Retroviral activation ofEvi-l gene expression is one of the most common transforming events in murine myeloid leukemias. To evaluate the role of the EVII gene in human acute myelogenous leukemia (AML), leukemic blasts or cell lines from 116 patients were examined. In eight patients the EVII gene was expressed and all but one had cytogenetically detectable translocations of chromosome 3q26 where the EVII gene has been localized. To identify breakpoints, a restriction map that spans 1700 kilobases (kb) of the EVII locus was developed by pulsed-field gel electrophoresis. In one case, t(3;3)(q21;q26), a rearrangement was localized to 170-330 kb 5' of the gene. In a second case, t(3;3)(q21;q26), there was a rearrangement 13 kb 5' of the gene. This rearrangement was cloned and shown to be due to the fusion of sequences from 3q21-22 with the EVII locus. In the third case, ins(3)-(q21q25q27), there was a rearrangement that mapped 150 kb downstream from the 5' end of the gene.Human acute myelogenous leukemia (AML) is associated with a number of recurring chromosomal abnormalities. Only recently have the genes associated with these cytogenetic changes been identified. One region of recurring abnormalities involves chromosome band 3q26 and includes t(3;3)(q21 ;q26), inv(3)(q21q26), t(2;3)(p21 ;q26), t(3;21)(q26;q22), and t(3 ;5)(q25
Constitutive phosphatidylinositol 3-kinase (PI3K)-AKT activation has a causal role in adult T-cell leukaemia-lymphoma (ATLL) and other cancers. ATLL cells do not harbour genetic alterations in PTEN and PI3KCA but express high levels of PTEN that is highly phosphorylated at its C-terminal tail. Here we report a mechanism for the N-myc downstream-regulated gene 2 (NDRG2)-dependent regulation of PTEN phosphatase activity via the dephosphorylation of PTEN at the Ser380, Thr382 and Thr383 cluster within the C-terminal tail. We show that NDRG2 is a PTEN-binding protein that recruits protein phosphatase 2A (PP2A) to PTEN. The expression of NDRG2 is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway. Given the high incidence of T-cell lymphoma and other cancers in NDRG2-deficient mice, PI3K-AKT activation via enhanced PTEN phosphorylation may be critical for the development of cancer.
Adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) infection, occurs in 2% to 4% of the HTLV-1 carriers with a long latent period, suggesting that additional alterations participate in the development of ATL. To characterize and identify novel markers of ATL, we examined the expression profiles of more than 12 000 genes in 8 cases of acute-type ATL using microarray. One hundred ninety-two genes containing interleukin 2 (IL-2) receptor ␣ were up-regulated more than 2-fold compared with CD4 ؉ and CD4 ؉ CD45RO ؉ T cells, and tumor suppressor in lung cancer 1 (TSLC1), caveolin 1, and prostaglandin D2 synthase showed increased expression of more than 30-fold.
We have identified a novel gene MEL1 (MDS1/EVI1-like gene 1) encoding a zinc finger protein near the breakpoint of t(1; 3)(p36;q21)-positive human acute myeloid leukemia (AML) cells. Here, we studied the structure, expression pattern, and function of MEL1 in leukemia cells. In this study, we have identified 3 transcription start sites, 1 in exon 1 and 2 in exon 2, and 2 kinds of translation products, 170 kDa (MEL1) and 150 kDa (MEL1S). Notably, the 150-kDa band of MEL1S was detected mainly in the t(1;3)(p36;q21)-positive AML cells. By immunoblot analysis and proteolytic mapping, it is suggested that the 150-kDa band of MEL1S in the leukemia cells is translated from the internal initiation codon ATG597 in exon 4 and is mostly lacking the amino-terminal PR domain of MEL1. By the cyclic amplification and selection of targets (CASTing) method for identifying consensus sequences, it was shown that the consensus sequences of MEL1 were included in 2 different consensus sequences for DNA-binding domain 1 and 2 (D1-CONS and D2-CONS) of EVI1. In reporter gene assays, MEL1S activated transcription via binding to D2-CONS; however, the fusion of MEL1 or MEL1S to GAL4 DNA-binding domain (DBD) made them GAL4 binding sitedependent transcriptional repressors. IntroductionThe PRDI-BF1-RIZ1 homologous (PR) domain is a newly recognized amino-terminal module 1 and was first noted for the homologous 100-amino acid region shared between positive regulatory domain I binding factor 1 (PRDI-BF1) (PRDM1) 2 and retinoblastoma-interacting zinc finger protein (RIZ) (PRDM2). 1 PR domain members (PRDMs) are also known to be in the suppressor of var, enhancer of zeste and trithorax (SET) domain superfamily. 3 RIZ is isolated by protein-protein interaction with the retinoblastoma tumor suppressor protein (Rb). 1 Consistent with a potential role in the Rb pathway, RIZ may play an important role in the pathogenesis of human cancer. Interestingly, RIZ produces 2 different gene products, a full-length RIZ1 and a short-form RIZ2 lacking a PR domain at the amino-terminus, which is generated by an alternative transcript derived from an internal promoter. 4 Both transcripts are widely expressed in many organs. However, recent study revealed that the expression rate of RIZ1 is decreased or several point mutations in the RIZ1 coding region exist in many kinds of tumors, suggesting that RIZ1 with a PR domain is a candidate tumor suppressor gene. 5,6 Murine ecotropic virus integration 1 site (Evi-1) zinc finger protein was isolated from common sites of viral integration in murine myeloid leukemia. 7 The human homolog, EVI1 at chromosomal position 3q26, is also transcriptionally activated by several recurrent chromosomal aberrations in acute myeloid leukemia (AML). 8 The most frequent rearrangements are t(3;3)(q21;q26) and inv(3)(q21q26) associated with AML (3q21q26 syndrome) and myelodysplastic syndrome (MDS). 8 A PR domain was later found in the MDS1/EVI1 gene product, which is derived from one of the EVI1 alternative transcripts. 9 The genomic region of ...
Acute myeloid leukemia with high ecotropic viral integration site-1 expression (EVI1(high) AML) is classified as a refractory type of leukemia with a poor prognosis. To provide new insights into the prevention and treatment of this disease, we identified the high expression of EVI1-regulated G protein-coupled receptor 56 (GPR56), and the association of high cell adhesion and antiapoptotic activities in EVI1(high) AML cells. Knockdown of GPR56 expression decreased the cellular adhesion ability through inactivation of RhoA signaling, resulting in a reduction of cellular growth rates and enhanced apoptosis. Moreover, in Gpr56(-/-) mice, the number of hematopoietic stem cells (HSCs) was significantly decreased in the bone marrow (BM) and, conversely, was increased in the spleen, liver and peripheral blood. The number of Gpr56(-/-) HSC progenitors in the G0/G1-phase was significantly reduced and was associated with impaired cellular adhesion. Finally, the loss of GPR56 function resulted in a reduction of the in vivo repopulating ability of the HSCs. In conclusion, GPR56 may represent an important GPCR for the maintenance of HSCs by acting as a co-ordinator of interactions with the BM osteosteal niche; furthermore, this receptor has the potential to become a novel molecular target in EVI1(high) leukemia.
Chromosome translocations involving band 12p13 are known to be involved in a variety of hematologic malignancies, some of them resulting in rearrangement of the ETV6/TEL gene. Applying the fluorescence in situ hybridization (FISH) method, we found a cryptic translocation t(12;15)(p13;q25) in an adult acute myeloid leukemia (AML) patient. Hybridization with cosmid probes showed that the ETV6 gene was rearranged in this translocation. A patient-specific cDNA library was screened with ETV6 cDNA, and a novel fusion transcript was identified between the ETV6 andTRKC/NTRK3 gene located on 15q25. TRKC is a receptor tyrosine kinase that is activated by neurotrophin-3 (NT-3). It is known to be expressed broadly in neural tissues but not in hematologic cells, so far. ETV6-TRKC chimeric transcript encoded the pointed (PNT) domain of the ETV6 gene that fused to the protein-tyrosine kinase (PTK) domain of the TRKC gene. Two types of fusion transcript were determined, one that included the entire PTK domain of TRKC and the other in which the 3′-terminal 462 bp of TRKC was truncated within the PTK domain. Western blot analysis showed the expression of both chimeric proteins of 52 and 38 kD in size. Our results suggest that chimeric PTK expressed in the leukemic cells may contribute to cellular transformation by abnormally activating TRK signaling pathways. Moreover, this is the first report on truncated neurotrophin receptors associated in leukemia.
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