Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines

Imatani, Akira; Callahan, Robert

doi:10.1038/sj.onc.1203295

Cited by 97 publications

(73 citation statements)

References 35 publications

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“…Aberrant Notch signalling can be detected in a wide variety of human tumors, such as mammary carcinoma and leukemia (Imatani and Callahan, 2000;Callahan and Egan, 2004;Grabher et al, 2006). Notch can either suppress or promote tumors depending on the cell type and context (Fan et al, 2004;Mansour et al, 2006;Vacca et al, 2006;Zhu et al, 2006;O'Neill et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

DAPT Enhances the Apoptosis of Human Tongue Carcinoma Cells

et al. 2009

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Section: Introductionmentioning

confidence: 99%

DAPT Enhances the Apoptosis of Human Tongue Carcinoma Cells

et al. 2009

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“…Inhibiting Notch signalling by overexpression of Numb reverts the transformed phenotype of MCF-7 cells (Stylianou et al, 2006), whereas silencing of Notch 3 inhibits proliferation and promotes apoptosis in ErbB2-negative breast cancer cell lines (Yamaguchi et al, 2008). Moreover, overexpression of Notch in non-tumourigenic breast epithelial cells induces transformation in vitro (Imatani and Callahan, 2000;Stylianou et al, 2006). Thus, deregulation of Notch signalling plays a significant role in tumorigenesis.…”

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confidence: 99%

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

et al. 2009

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g-Secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their intracellular domains to the nucleus. Notch overexpression has been associated with breast, colon, cervical and prostate cancers. We tested the effect of three different g-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 mM and above but had a minimal effect on the non-malignant breast lines. GSI1 was also cytotoxic for a wide variety of cancer cell lines in the NCI60 cell screen. GSI1 treatment resulted in a marked decrease in g-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the g-secretase components or ligands. Flow cytometric and western blot analyses indicated that GSI1 induces a G2/M arrest leading to apoptosis, through downregulation of Bcl-2, Bax and Bcl-XL. GSI1 also inhibited proteasome activity. Thus, the g-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent a novel therapy in breast cancer.

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“…NEXT or N1 NICD (13)(14)(15)(16)(17)(18) suggesting that regardless of the final nuclear target(s), Notch proteolysis is a key to neoplastic transformation as well as normal activity of these genes.…”

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confidence: 99%

Murine Notch Homologs (N1–4) Undergo Presenilin-dependent Proteolysis

Saxena¹,

Schroeter²,

Mumm³

et al. 2001

Journal of Biological Chemistry

163

120

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Oncogenic forms of Notch1, Notch2, and Notch4 appear to mimic signaling intermediates of Notch1 and suggest that the role of proteolysis in Notch signaling has been conserved. Here we demonstrate that extracellularly truncated Notch homologs are substrates for a presenilin-dependent ␥-secretase activity. Despite minimal conservation within the transmembrane domain, the requirement for a specific amino acid (P1 valine) and its position at the cleavage site relative to the cytosolic border of the transmembrane domain are preserved. Cleaved, untethered Notch intracellular domains from each receptor translocate to the nucleus and interact with the transcriptional regulatory protein CSL. All four Notch proteins display presenilin-dependent transactivating potential on a minimal promoter reporter. Thus, this study increases the number of biochemically characterized ␥-secretase substrates from two to five. Despite a high degree of structural homology and the presenilin-dependent activity of truncated Notch proteins, the extent that this reflects functional redundancy is unknown.

show abstract

Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines

Cited by 97 publications

References 35 publications

DAPT Enhances the Apoptosis of Human Tongue Carcinoma Cells

DAPT Enhances the Apoptosis of Human Tongue Carcinoma Cells

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

Murine Notch Homologs (N1–4) Undergo Presenilin-dependent Proteolysis

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