|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.
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
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.
2 Dotto, G P. "Notch tumor suppressor function." Oncogene 27.38 (2008): 5115-5123. Oncogene. Web. 10 May 2014.
3 Lobry, Camille, Philmo Oh, and Iannis Aifantis. "Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think." JEM 208.10 (2011): 1931-1935. JEM. Web. 2 May 2015.
4 Radtke, Freddy, and Kenneth Raj. "The role of Notch in tumorigenesis: oncogene or tumour suppressor?." Nature Reviews Cancer 3.10 (2003): 756-767. NCBI. Web. 10 May 2014.