Notch signaling mediates G 1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases

Ila Joshi, Lisa M. Minter, Janice Telfer, Renée M. Demarest, Anthony J. Capobianco, Jon C. Aster, Piotr Sicinski, Abdul Fauq, Todd E. Golde, Barbara A. Osborne

Research output: Contribution to journalArticle

113 Scopus citations

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 mechanismsby 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 7-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.

Original languageEnglish (US)
Pages (from-to)1689-1698
Number of pages10
JournalBlood
Volume113
Issue number8
DOIs
StatePublished - Feb 19 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Joshi, I., Minter, L. M., Telfer, J., Demarest, R. M., Capobianco, A. J., Aster, J. C., Sicinski, P., Fauq, A., Golde, T. E., & Osborne, B. A. (2009). Notch signaling mediates G 1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood, 113(8), 1689-1698. https://doi.org/10.1182/blood-2008-03-147967