Linked Life Data

12560229

Source:http://linkedlifedata.com/resource/pubmed/id/12560229

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2003-5-6
pubmed:abstractText
Macrophage inflammatory protein-1alpha (MIP-1alpha) is produced in high concentration by multiple myeloma (MM) cells in about 70% of patients, and MIP-1alpha levels correlate with their disease activity. Patients who have high levels of MIP-1alpha have a poor prognosis. Furthermore, blocking MIP-1alpha expression in an in vivo model of human MM profoundly decreases both tumor burden and bone destruction, suggesting that MIP-1alpha is an important mediator of MM bone disease. Therefore, to analyze the regulation of MIP-1alpha production in MM, we cloned the human MIP-1alpha promoter and characterized the transcription factor (TF) motifs that control MIP-1alpha expression in MM cells. The proximal region of MIP-1alpha promoter was composed of 2 sets of identical transcription regulatory regions consisting of GATA-2(+) AML-1(+) C/EBPalpha motifs. Since 2 alternatively spliced variants of the acute myeloid leukemia-1 (AML-1) class of TFs can bind the AML-1 region, AML-1A and AML-1B, the relationship between the expression levels of AML-1A or AML-1B in MM cells and their capacity to express MIP-1alpha was examined. AML-1A mRNA was relatively overexpressed compared with AML-1B in MM cell lines that produced high levels of MIP-1alpha (> 1 ng/mL per 10(6) cells per 72 hours), but AML-1A was not increased in MM cell lines that expressed less than 200 pg/mL MIP-1alpha. More importantly, the ratio of AML-1A to AML-1B mRNA levels was also increased in 3 of 3 highly purified myeloma cells from patients with MM who expressed increased amounts of MIP-1alpha. The ratio of AML-1A to AML-1B mRNA in patients with MM was 8-fold higher than in healthy controls. Transduction of AML-1B into the MM-derived MM.1S and ARH-77 cells totally blocked MIP-1alpha production, while AML-1A did not further increase the already high levels of MIP-1alpha produced by these cells. Taken together, these data demonstrate that in patients with MM who produce increased concentrations of MIP-1alpha, the relative level of AML-1B is significantly decreased compared with healthy controls. The data suggest that strategies that enhance AML-1B expression or decrease AML-1A in MM cells may be beneficial therapeutically.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0006-4971
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
101
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3778-83
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:12560229-Base Sequence, pubmed-meshheading:12560229-Cells, Cultured, pubmed-meshheading:12560229-Chemokine CCL3, pubmed-meshheading:12560229-Chemokine CCL4, pubmed-meshheading:12560229-Cloning, Molecular, pubmed-meshheading:12560229-Core Binding Factor Alpha 2 Subunit, pubmed-meshheading:12560229-DNA-Binding Proteins, pubmed-meshheading:12560229-Gene Expression Regulation, Neoplastic, pubmed-meshheading:12560229-HL-60 Cells, pubmed-meshheading:12560229-Humans, pubmed-meshheading:12560229-Macrophage Inflammatory Proteins, pubmed-meshheading:12560229-Molecular Sequence Data, pubmed-meshheading:12560229-Multiple Myeloma, pubmed-meshheading:12560229-Promoter Regions, Genetic, pubmed-meshheading:12560229-Protein Isoforms, pubmed-meshheading:12560229-Proto-Oncogene Proteins, pubmed-meshheading:12560229-RNA, Messenger, pubmed-meshheading:12560229-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:12560229-Transcription, Genetic, pubmed-meshheading:12560229-Transcription Factors, pubmed-meshheading:12560229-Tumor Cells, Cultured, pubmed-meshheading:12560229-U937 Cells
pubmed:year
2003
pubmed:articleTitle
AML-1A and AML-1B regulation of MIP-1alpha expression in multiple myeloma.
pubmed:affiliation
Department of Medicine Hematology/Oncology, University of Pittsburgh, PA, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't