Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases

Abstract

IntroductionNotch proteins are a family of ligand-activated large (300 kDa) single-pass transmembrane heterodimeric receptors. 1 Notch controls multiple cell fate decisions and differentiation processes during lymphocyte development and function and is required at various stages of T-cell development. 2,3 Deregulated Notch signaling during T-cell development leads to malignant transformation, including the cancer most closely associated with aberrant Notch expression in humans, acute T-cell acute lymphoblastic leukemia (T-ALL), which constitutes approximately 15% to 20% of ALLs seen in adults and children. 4,5 The oncogenic potential of Notch was first identified in (t7;9) chromosomal rearrangement in approximately 2% of human T-ALL, whereby intracelluar Notch1 is translocated to the T-cell receptor (TCR) ␤ gene. 6 More than 50% of human T-ALLs bear mutations in Notch1, indicating a prominent role for Notch in this T-cell malignancy. 7 Inhibitors of Notch signaling abrogate the growth of human and murine T-ALL cell lines bearing Notch1 gain-of-function mutations, indicating Notch is required in established tumors. 8,9 In vertebrates, 4 notch receptors (Notch 1-4) are activated by 5 different Notch ligands expressed on various cell types: Jagged1, Jagged2, and Delta-like (DL)1, DL3, and DL4. 2,3 After ligandbinding, proteolytic cleavage by ␥-secretase releases the signalingcompetent intracellular domain of Notch (N IC ). 10-12 N IC is composed of a RAM domain, ankyrin repeats (ANK) that mediate protein-protein interactions, nuclear localization sequences, a transactivation domain (TAD), and a C-terminal PEST domain regulating protein turnover. Human T-ALL cases frequently bear activating mutations in the extracellular heterodimerization domain and/or the C-terminal PEST domain of Notch1, resulting in ligand-independent activation. 7 During canonical Notch signaling, N IC translocates to the nucleus, engages its nuclear binding protein CSL (CBF-1, mammals; suppressor of hairless, Drosophila melanogaster; Lag-1, Caenorhabditis elegans) and transcribes downstream target genes, including the HES family of transcriptional repressors. 13,14 In the absence of N IC , CSL recruits repressor complexes to the regulatory regions of Notch/CSL target genes, inhibiting transcription. N IC interaction with CSL acts as a switch that promotes the assembly of CSL coactivator complexes. [15][16][17] ␥-Secretase inhibitors (GSIs) block proteolytic cleavage of Notch receptors, thereby preventing activation of Notch. Use of GSI in activated T cells results in down-regulation of nuclear factor (NF)-B activity, cytokine (interleukin-2 [IL-2] and interferon-␥ [IFN-␥]) production, and cell proliferation. 18 In T-cell lymphomas, context-specific putative target genes have been identified through which Notch1 may promote transformation by altering cell-growth kinetics. [19][20][21] The D-type cyclins (cyclins D1, D2, and D3) are the first cyclins to be induced as cells enter the G 1 phase of the cell cycle, [22][23][24] and, thus, if regulat...

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

“…The former included CCND3, which encodes a cyclin necessary for G1/G2 transition (39) via direct binding to the gene promoter, consistent with a previous report in T-ALL (40). Among the latter, BCL2 and MCL1, two antiapoptotic genes with a well-established role in the pathogenesis of CLL, emerged as novel targets of NOTCH1, likely regulated through long-range dynamic interactions (24,(41)(42)(43).…”

Dynamic binding of RBPJ is determined by Notch signaling status

“…Isolated examples in the literature reported enhanced RBPJ binding on the promoters of cyclin D3 and Hes1 in mammalian cells following Notch pathway activation (Fryer et al 2004;Joshi et al 2009). In those studies, enriched RBPJ occupancies were shown by semiquantitative PCR analysis on chromatin-immunopurified material.…”

Notch controls the magnitude of T helper cell responses by promoting cellular longevity

“…Conflicting reports exist about the role of Notch in CD4 + T-cell expansion. Some studies concluded that Notch stimulates proliferation of CD4 + T cells; others found it to be inhibitory (13)(14)(15)(16)(17). Notch may have distinct roles in CD4 + T cells under different conditions, but some of the reported discrepancies might stem from experimental factors.…”

“…Notch may have distinct roles in CD4 + T cells under different conditions, but some of the reported discrepancies might stem from experimental factors. For instance, some studies targeted the γ-secretase, which does not selectively affect cleavage of Notch only, but also of other substrates (15)(16)(17)(18). Also, antibody-mediated activation of Notch may not faithfully mimic the function of natural ligands (15).…”