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 language | English |
|---|---|
| Pages (from-to) | 1689-1698 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 113 |
| Issue number | 8 |
| DOIs | |
| State | Published - Feb 19 2009 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Notch signaling mediates G 1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases
AU - Joshi, Ila
AU - Minter, Lisa M.
AU - Telfer, Janice
AU - Demarest, Renée M.
AU - Capobianco, Anthony J
AU - Aster, Jon C.
AU - Sicinski, Piotr
AU - Fauq, Abdul
AU - Golde, Todd E.
AU - Osborne, Barbara A.
PY - 2009/2/19
Y1 - 2009/2/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=61849087835&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=61849087835&partnerID=8YFLogxK
U2 - 10.1182/blood-2008-03-147967
DO - 10.1182/blood-2008-03-147967
M3 - Article
C2 - 19001083
AN - SCOPUS:61849087835
VL - 113
SP - 1689
EP - 1698
JO - Blood
JF - Blood
SN - 0006-4971
IS - 8
ER -