 |
| Dual role of Notch signaling in cancer |
The table above originates from a review article titled, Oncogenic and Tumor suppressor functions ofNotch in cancer: It’s NOTCH what you think, which was published in The
Journal of Experimental Medicine. This table is essentially the overall
theme of our Cancer project showing how the role of the Notch signaling pathway
can play both the role of an oncogene and the role of a tumor suppressor gene,
depending on the type of cancer.3
Since looking at all of these cancers is a little too
ambitious for this time period permitted, we will go over the different roles
of the Notch signaling pathway in both T-cell Leukemia and HNSCC. As seen from
the graph above, Notch in T-cell Leukemia acts as an oncogene while in HNSCC
acts as a tumor suppressor. However, to fully understand what makes Notch
either an oncogene or a tumor suppressor, we first must cover Notch’s normal
function within a cell.
 |
| Notch signalling. Notch proteins are synthesized as precursor proteins that are processed by a furin-like convertase in the Golgi before being transported to the cell surface, where they reside as heterodimers. Interaction of Notch receptors with their ligands, such as Delta-like or Jagged, leads to a cascade of proteolytic cleavages. The first cleavage is mediated by TACE (tumour-necrosis factor-α-convering enzyme/metalloproteinase), followed by a second cleavage mediated by the γ-secretase activity of presenilins (PS), which liberates the cytoplasmic domain —Notch intracellular domain (NIC) — of the Notch receptors. The liberated NIC enters the nucleus and binds to the transcription factor CSL, which displaces co-repressors (CoR) and recruits co-activators (CoA), leading to transcriptional activation of downstream target genes. This pathway is known as the CSL-dependent pathway. Genetic evidence points to the existence of a CSL-independent pathway that is poorly characterized at present. |
The figure above is from another
review article called, The Role of Notchin Tumorigenesis: Oncogene or Tumour Suppressor? As seen here, Notch genes
code for a heterodimer protein that consists of both an apical and cytoplasmic
subunit. The apical subunit consists of EGF-like repeats that act as a receptor
for certain ligands while the cytoplasmic subunit acts as a promoter that
activates certain genes that promotes cell differentiation.4 Likewise, Notch can
also inhibit other signaling pathways, such as Wnts, which promotes cell
cycling.2
In a different article, Analysis of DNA Surrounding the Breakpoints of ChromosomalTranslocations Involving the p T Cell Receptor Gene in Human LymphoblasticNeoplasms, it is found that most T-Cell Leukemia have
a chromosomal translocation between chromosome 7 and chromosome 9.5 Essentially
what happens is that a part of Chromosome 7 breaks off and attaches to
chromosome 9. This is significant, however, because at the point at which
chromosome 7 breaks off is in EFG-like repeat region of the NOTCH1 gene.
Therefore when NOTCH1 is transcribed, instead of creating a proficient NOTCH1
protein, it creates a truncated version of it known as NOTCH1-IC. NOTCH1-IC
causes a normal growing T cell to turn into a premature DP T cell that develops
into aggressive monoclonal T cell tumors. It is not clear on exactly how
NOTCH1-IC transforms these normal T cells into cancerous tumors, but there is
evidence in mice that NOTCH1-IC specifically causes this reaction in T-cell
signals.4
 |
| Notch1 induction of extrathymic DP T cells requires pre-TCR assembly and signaling. Progenitor cells from wild-type, Rag-2/, Rag-2/ TCR, and SLP-76 mice were trans- duced with MigR1 control or MigR1-ICN1 viruses and then transferred to lethally irradiated C57BL/6 recipients. BM cells were stained 20–30 d after trans- fer with the indicated antibodies and analyzed by flow cytometry. GFP gates were set as described in Materials and Methods. The CD4 and CD8 SP thymocytes present in all GFP populations are recipient derived, as shown by prior congenic analysis (data not shown). Data are representa- tive of 3–12 recipients for each donor genotype. |
This
figure is taken from the article, Separation of Notch1 Promoted LineageCommitment and Expansion/Transformation in Developing T Cells. Essentially this figure shows that a tumor
will only form from NOTCH1-IC in T-cells where the TcRβ receptor is present, which is in usually all functioning T cells.1 The sample size is a little questionable being 3-12 for each donor genotype.
However, I believe that this evidence is significant due to the absolute lack
of tumor in all genotypes except those that are TcRβ positive. This means that NOTCH1-IC causes this specific tumor formation specifically in T cell Leukemia. Understanding
this specificity, a good therapy could target this signaling system in hopes to
prevent, halt, or even decrease the size of tumors in T cell leukemia.
Work Cited:
1 Allman, D., J. C. Aster, J. C. Pui, G. A. Koretzky, P. Myung, L. Xu, S. Bakkour, J. A. Punt, F. G. Karnell, and W. S. Pear. "Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells." Journal of Experimental Medicine194.1 (2001): 99-106.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193437/pdf/010215.pdf. Web. 8 May 2014.