The putative oncoprotein Bcl-3 induces cyclin D1 to stimulate G(1) transition.
Bcl-3 is a distinctive member of the IkappaB family of NF-kappaB inhibitors because it can function to coactivate transcription. A potential involvement of Bcl-3 in oncogenesis is highlighted by the fact that it was cloned due to its location at a breakpoint junction in some cases of human B-cell chronic lymphocytic leukemia and that it is highly expressed in human breast tumor tissue. To analyze the effects of Bcl-3 dysregulation in breast epithelial cells, we created stable immortalized human breast epithelial cell lines either expressing Bcl-3 or carrying the corresponding vector control plasmid. Analysis of the Bcl-3-expressing cells suggests that these cells have a shortened G(1) phase of the cell cycle as well as a significant increase in hyperphosphorylation of the retinoblastoma protein. Additionally, the cyclin D1 gene was found to be highly expressed in these cells. Upon further analysis, Bcl-3, acting as a coactivator with NF-kappaB p52 homodimers, was demonstrated to directly activate the cyclin D1 promoter through an NF-kappaB binding site. Therefore, our results demonstrate that dysregulated expression of Bcl-3 potentiates the G(1) transition of the cell cycle by stimulating the transcription of the cyclin D1 gene in human breast epithelial cells.
Westerheide
S D
SD
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Mayo
M W
MW
Anest
V
V
Hanson
J L
JL
Baldwin
A S
AS
D016475:3T3 Cells; D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism; D019556:COS Cells; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D003001:Cloning, Molecular; D019938:Cyclin D1 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015448:Leukemia, B-Cell / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D019938:Cyclin D1; D008156:Luciferases