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1.
Blood Cancer J ; 1(11): e43, 2011 Nov.
Article in English | MEDLINE | ID: mdl-22829079

ABSTRACT

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that ß-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/ß-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished ß-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.

2.
Gene ; 278(1-2): 131-9, 2001 Oct 31.
Article in English | MEDLINE | ID: mdl-11707330

ABSTRACT

Homeotic proteins are transcription factors that regulate the expression of multiple genes involved in development and differentiation. We previously isolated a cDNA encoding such a protein from the human leukemia cell line K562, termed Beta Protein 1 (BP1), which is involved in negative regulation of the human beta-globin gene. Sequence comparison revealed that BP1 is a member of the distal-less (DLX) family of homeobox genes and that it shares its homeodomain and 3' sequences with another DLX cDNA, DLX7. BP1 and DLX7 exhibit unique 5' regions, diverging at nucleotide 565 of BP1. We mapped this new distal-less family member BP1 to chromosome 17q21-22 by FISH and PCR, which is the same locus to which DLX7 has been mapped. These results strongly suggest that BP1 and DLX7 are isoforms (derived from the same gene). Since our previous data demonstrated that BP1 and DLX7 are frequently co-expressed, we determined whether DLX7 is also involved in the negative regulation of the beta-globin gene. Mobility shift assays demonstrated that both BP1 and DLX7 proteins, synthesized in vitro, bind to the same BP1 binding site. However, using transient assays, we showed that although BP1 represses activity of a reporter gene through either of two silencer DNA sequences upstream of the beta-globin gene, DLX7 did not show repressor activity against the beta-globin promoter. Further characterization of these apparent isoforms is of significance since they are jointly expressed in acute myeloid leukemia and in many leukemia cell lines.


Subject(s)
Globins/genetics , Homeodomain Proteins/physiology , Oncogene Proteins , Transcription Factors , Base Sequence , Chromosomes, Human, Pair 17/genetics , Gene Expression Regulation , Genes, Homeobox/genetics , Genes, Homeobox/physiology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , In Situ Hybridization, Fluorescence , K562 Cells , Molecular Sequence Data , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Isoforms/physiology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/physiology , Sequence Alignment , Sequence Homology, Nucleic Acid
3.
Am J Hematol ; 60(1): 27-35, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9883803

ABSTRACT

Proteins involved in repression of the human beta-globin gene may be useful in the treatment of sickle cell anemia, in conjunction with therapy to reactivate fetal globin genes. If there is a reciprocal elevation of gamma-globin expression upon repression, this approach could be useful in additional hemoglobinopathies. We previously showed that repression of the beta-globin gene appears to be mediated through two DNA sequences, silencers I and II, and identified a protein termed BP1 which binds to both silencer sequences. In this study, we cloned two cDNAs encoding proteins which bind to an oligonucleotide in silencer I containing a BP1 binding site. These cDNAs correspond to HMG-I and HMG-Y, isoforms regarded as architectural proteins. We demonstrate that binding of HMG-I(Y) to this oligonucleotide causes bending/flexure of the DNA. HMG-I(Y) also binds to a second oligonucleotide containing a BP1 binding site located in a negative control region upstream of the delta-globin gene, suggesting a role for HMG-I(Y) in repression of adult globin genes. Expression studies revealed that HMG-I(Y) is ubiquitously expressed in human tissues that do not express beta-globin, being present in 48 of 50 tissues and six hematopoietic cell lines examined. Furthermore, HMG-I(Y) expression is down-regulated during differentiation of primary erythroid cells. We present a model in which HMG-I(Y) alters DNA conformation to allow binding of repressor proteins, and in which the relative amount of HMG-I(Y) helps to determine the repressive state of the beta-globin gene.


Subject(s)
Globins/genetics , Globins/metabolism , High Mobility Group Proteins/genetics , High Mobility Group Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Blotting, Northern , Cell Differentiation/physiology , DNA-Binding Proteins/genetics , Erythrocytes/cytology , HMGA1a Protein , Humans , RNA, Messenger/metabolism , Tissue Distribution , Transcription, Genetic/genetics
4.
Mod Pathol ; 11(10): 957-62, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9796722

ABSTRACT

Telomerase is a ribonucleoprotein that uses its internal RNA component as a template for synthesis of telomeric DNA on the ends of chromosomes after each round of cell division. It is expressed in approximately 90% of all human cancers tested to date, as well as in most immortal cell lines. Recently, telomerase activity was detected in normal proliferating lymphoid tissue and in non-Hodgkin's lymphomas (NHLs) by use of the telomeric repeat amplification protocol assay, a qualitative measure of telomerase activity. In this study, we modified the assay to measure quantitatively the telomerase activity in lymph node biopsy specimens obtained from patients with lymphadenopathy. The lymph nodes either contained benign reactive changes, were involved by NHL of B-cell lineage, or were involved by Hodgkin's disease. Telomerase activity was detected in all of our samples, benign as well as malignant. The levels of activity were unaffected by the patient's human immunodeficiency virus-1 status. Although the specimens involved by NHLs showed a range in telomerase activity from low to high, the levels did not correlate strictly with the histologic grade according to the Working Formulation. All of the cases of Hodgkin's disease also expressed telomerase activity, and the levels were similar regardless of histologic subtype. Our results showed that telomerase activity was expressed in both benign and malignant lymphoproliferative processes.


Subject(s)
HIV Infections/enzymology , HIV-1 , Hodgkin Disease/pathology , Lymphoma, AIDS-Related/pathology , Telomerase/analysis , Biopsy , DNA Primers/chemistry , Electrophoresis, Polyacrylamide Gel , HIV Infections/pathology , Hodgkin Disease/enzymology , Humans , Lymph Nodes/enzymology , Lymph Nodes/pathology , Lymphoma, AIDS-Related/enzymology , Polymerase Chain Reaction , Tumor Cells, Cultured/enzymology , Tumor Cells, Cultured/pathology
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