Abstract
Notch signaling plays a role in normal lymphocyte development and function. Activating Notch1-mutations, leading to aberrant downstream signaling, have been identified in human T-cell acute lymphoblastic leukemia (T-ALL). While this highlights the contribution of Notch signaling to T-ALL pathogenesis, the mechanisms by which Notch regulates proliferation and survival in normal and leukemic T cells are not fully understood. Our findings identify a role for Notch signaling in G(1)-S progression of cell cycle in T cells. Here we show that expression of the G(1) proteins, cyclin D3, CDK4, and CDK6, is Notch-dependent both in vitro and in vivo, and we outline a possible mechanism for the regulated expression of cyclin D3 in activated T cells via CSL (CBF-1, mammals; suppressor of hairless, Drosophila melanogaster; Lag-1, Caenorhabditis elegans), as well as a noncanonical Notch signaling pathway. While cyclin D3 expression contributes to cell-cycle progression in Notch-dependent human T-ALL cell lines, ectopic expression of CDK4 or CDK6 together with cyclin D3 shows partial rescue from gamma-secretase inhibitor (GSI)-induced G(1) arrest in these cell lines. Importantly, cyclin D3 and CDK4 are highly overexpressed in Notch-dependent T-cell lymphomas, justifying the combined use of cell-cycle inhibitors and GSI in treating human T-cell malignancies.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / enzymology*
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CD4-Positive T-Lymphocytes / pathology
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Cell Line, Tumor
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Cyclin D3
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Cyclin-Dependent Kinase 4 / genetics
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Cyclin-Dependent Kinase 4 / metabolism*
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Cyclin-Dependent Kinase 6 / genetics
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Cyclin-Dependent Kinase 6 / metabolism*
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Cyclins / metabolism*
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G1 Phase / physiology
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Gene Expression Regulation, Leukemic
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Gene Expression Regulation, Neoplastic
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Humans
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Lymphoma, T-Cell / enzymology
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Lymphoma, T-Cell / pathology
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Mice
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Mice, Inbred C57BL
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NF-kappa B / metabolism
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Phosphorylation / physiology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Promoter Regions, Genetic / physiology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Receptor, Notch2 / genetics
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Receptor, Notch2 / metabolism
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Receptor, Notch3
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Receptor, Notch4
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Receptors, Notch / genetics
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Receptors, Notch / metabolism
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Retinoblastoma Protein / metabolism
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S Phase / physiology
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Signal Transduction / physiology
Substances
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CCND3 protein, human
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Ccnd3 protein, mouse
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Cyclin D3
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Cyclins
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NF-kappa B
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Notch1 protein, mouse
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Notch2 protein, mouse
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Notch3 protein, mouse
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Proto-Oncogene Proteins
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Receptor, Notch1
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Receptor, Notch2
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Receptor, Notch3
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Receptor, Notch4
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Receptors, Notch
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Retinoblastoma Protein
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Notch4 protein, mouse
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Cdk4 protein, mouse
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Cdk6 protein, mouse
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6