BCL-1/cyclin D1 oncoprotein oscillates and subverts the G1 phase control in B-cell neoplasms carrying the t(11;14) translocation.
In an effort to elucidate the biological role played by cyclin D1, a candidate BCL-1 oncogene, in human B-cell tumours carrying the t(11;14) translocation, we have studied the properties of this cyclin protein in a series of human lymphoid lines with rearrangements in the BCL-1 locus. The BCL-1/cyclin D1 protein was easily detectable in both immunocytochemistry and immunoblotting, its abundance grossly correlating with the mRNA levels. The cyclin D1 protein was localised predominantly to nuclei and there was a striking variation of staining intensity among the exponentially growing cells, reflecting the maximum level reached in mid/late G1 and the lowest level in S-phase. This characteristic mode of cell cycle-dependent oscillation was confirmed by three independent approaches, demonstrating that even upon rearrangement, the expression of cyclin D1 is regulated in a cyclical manner. Antibody-mediated and anti-sense oligonucleotide 'knockout' experiments revealed that the aberrantly expressed BCL-1/cyclin D1 protein is required for G1 phase progression of all four B-cell tumours with the BCL-1 rearrangement. Consistent with the proposed oncogenic role of this cyclin, our data demonstrate that the BCL-1 deregulation caused by chromosomal rearrangement leads to expression of a functionally active cyclin D1 protein which subverts the G1 phase control in the human B-cell tumours carrying the t(11;14) translocation.
Lukas
J
J
Danish Cancer Society, Division for Cancer Biology, Copenhagen.
Jadayel
D
D
Bartkova
J
J
Nacheva
E
E
Dyer
M J
MJ
Strauss
M
M
Bartek
J
J
D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D019938:Cyclin D1; D016213:Cyclins / Q000502:physiology*; D016193:G1 Phase; D006801:Humans; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D016213:Cyclins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1