Requirement for cyclin D3 in lymphocyte development and T cell leukemias.
The D-type cyclins (cyclins D1, D2, and D3) are components of the core cell cycle machinery in mammalian cells. Cyclin D3 gene is rearranged and the protein is overexpressed in several human lymphoid malignancies. In order to determine the function of cyclin D3 in development and oncogenesis, we generated and analyzed cyclin D3-deficient mice. We found that cyclin D3(-/-) animals fail to undergo normal expansion of immature T lymphocytes and show greatly reduced susceptibility to T cell malignancies triggered by specific oncogenic pathways. The requirement for cyclin D3 also operates in human malignancies, as knock-down of cyclin D3 inhibited proliferation of acute lymphoblastic leukemias deriving from immature T lymphocytes. These studies point to cyclin D3 as a potential target for therapeutic intervention in specific human malignancies.
Sicinska
Ewa
E
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Aifantis
Iannis
I
Le Cam
Laurent
L
Swat
Wojciech
W
Borowski
Christine
C
Yu
Qunyan
Q
Ferrando
Adolfo A
AA
Levin
Steven D
SD
Geng
Yan
Y
von Boehmer
Harald
H
Sicinski
Piotr
P
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015458:Leukemia, T-Cell / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C080336:CCND2 protein, human; C534696:CCND3 protein, human; C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)