Document Detail

Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15(INK4b) normally associated with differentiation.
MedLine Citation:
PMID:  11593429     Owner:  NLM     Status:  MEDLINE    
Deregulated expression of the proto-oncogene c-myb, which results from provirus integration, is thought to be responsible for transformation in a set of murine leukemia virus (MuLV)-induced myeloid leukemias (MML). We reported recently that this transcription factor promotes proliferation by directly transactivating c-myc and inhibits cell death through its up-regulation of Bcl-2 (Schmidt et al., 2000). To understand more about how these cells become transformed we looked at how they deal with cellular pathways inducing growth arrest. Specifically, we were interested in the expression of the tumor suppressor gene Cdkn2b (p15(INK4b)) in MML because this gene is expressed during myeloid differentiation and its inactivation by methylation has been shown to be important for the development of human acute myeloid leukemia. mRNA levels for p15(INK4b) and another INK4 gene p16(INK4a) were examined in monocytic Myb tumors and were compared with expression of the same genes in c-myc transformed monocytic tumors that do not express c-Myb. The Cdkn2a (p16(INK4a)) gene was generally not expressed in either tumor type, an observation explained by methylation or deletion in the promoter region. Although Cdkn2b (p15(INK4b)) mRNA was expressed in the Myc tumors, many transcripts were aberrant in size and contained only exon 1. Surprisingly, in the majority of the Myb tumors there was no p15(INK4b) transcription and neither deletion nor methylation could explain this result. Additional experiments demonstrated that, in the presence of constitutive c-Myb expression, the induction of p15(INK4b) mRNA that accompanies differentiation of M1 cells to monocytes does not occur. Therefore, the transcriptional regulator c-Myb appears to prevent activation of a growth arrest pathway that normally accompanies monocyte maturation.
M Schmidt; R Koller; P Haviernik; J Bies; K Maciag; L Wolff
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncogene     Volume:  20     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2001 Sep 
Date Detail:
Created Date:  2001-10-10     Completed Date:  2001-11-01     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  6205-14     Citation Subset:  IM    
Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD, USA.
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MeSH Terms
Blotting, Northern
Blotting, Western
Carrier Proteins / metabolism*
Cell Cycle Proteins*
Cell Differentiation
CpG Islands
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16*
DNA, Complementary / metabolism
Gene Expression Regulation, Neoplastic*
Genes, myc / genetics
Interleukin-6 / metabolism
Leukemia, Myeloid / metabolism*
Mice, Inbred BALB C
Models, Genetic
Polymerase Chain Reaction
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myb / metabolism*
RNA, Messenger / metabolism
Tumor Cells, Cultured
Tumor Suppressor Proteins*
Reg. No./Substance:
0/Carrier Proteins; 0/Cdkn2b protein, mouse; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p15; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/DNA, Complementary; 0/Interleukin-6; 0/Proto-Oncogene Proteins c-myb; 0/RNA, Messenger; 0/Tumor Suppressor Proteins

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