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

105 Citations (Scopus)

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

Fingerprint

Cyclin D3
T-cells
Cell Cycle
Phosphotransferases
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Cells
T-Lymphocytes
Cell Line
Amyloid Precursor Protein Secretases
T-Cell Lymphoma
Caenorhabditis elegans
Drosophila melanogaster
Mammals
Lymphocytes
Mutation
Survival
Neoplasms
Proteins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Joshi, I., Minter, L. M., Telfer, J., Demarest, R. M., Capobianco, A. J., Aster, J. C., ... 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

Notch signaling mediates G 1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. / Joshi, Ila; Minter, Lisa M.; Telfer, Janice; Demarest, Renée M.; Capobianco, Anthony J; Aster, Jon C.; Sicinski, Piotr; Fauq, Abdul; Golde, Todd E.; Osborne, Barbara A.

In: Blood, Vol. 113, No. 8, 19.02.2009, p. 1689-1698.

Research output: Contribution to journalArticle

Joshi, I, Minter, LM, Telfer, J, Demarest, RM, Capobianco, AJ, Aster, JC, Sicinski, P, Fauq, A, Golde, TE & Osborne, BA 2009, 'Notch signaling mediates G 1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases', Blood, vol. 113, no. 8, pp. 1689-1698. https://doi.org/10.1182/blood-2008-03-147967
Joshi, Ila ; Minter, Lisa M. ; Telfer, Janice ; Demarest, Renée M. ; Capobianco, Anthony J ; Aster, Jon C. ; Sicinski, Piotr ; Fauq, Abdul ; Golde, Todd E. ; Osborne, Barbara A. / Notch signaling mediates G 1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. In: Blood. 2009 ; Vol. 113, No. 8. pp. 1689-1698.
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