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<scene name='86/868190/Nrr_domain_alonecentre/2'>NRR</scene> mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of T-cell acute lymphoblastic leukemia (T-ALL)<ref> PMID: 15472075 </ref>. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" />
<scene name='86/868190/Nrr_domain_alonecentre/2'>NRR</scene> mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of T-cell acute lymphoblastic leukemia (T-ALL)<ref> PMID: 15472075 </ref>. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" />
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Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on [https://www.nature.com/articles/onc2016133#Abs1 NOTCH3-selective inhibitory antibodies].<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref>
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Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on NOTCH3-selective inhibitory antibodies <ref> PMID: 27157619</ref>.<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref>
== Relevance ==
== Relevance ==

Revision as of 16:33, 19 January 2022

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Crystal structure of Notch3 NRR

Drag the structure with the mouse to rotate

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133
  2. ↑ Guo Z, Ohlstein B. Stem cell regulation. Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. Science. 2015 Nov 20;350(6263). pii: 350/6263/aab0988. doi:, 10.1126/science.aab0988. PMID:26586765 doi:http://dx.doi.org/10.1126/science.aab0988
  3. ↑ Callahan R, Smith GH. MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene. 2000 Feb 21;19(8):992-1001. doi: 10.1038/sj.onc.1203276. PMID:10713682 doi:http://dx.doi.org/10.1038/sj.onc.1203276
  4. ↑ Aburjania Z, Jang S, Whitt J, Jaskula-Stzul R, Chen H, Rose JB. The Role of Notch3 in Cancer. Oncologist. 2018 Aug;23(8):900-911. doi: 10.1634/theoncologist.2017-0677. Epub, 2018 Apr 5. PMID:29622701 doi:http://dx.doi.org/10.1634/theoncologist.2017-0677
  5. ↑ Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004 Oct 8;306(5694):269-71. doi: 10.1126/science.1102160. PMID:15472075 doi:http://dx.doi.org/10.1126/science.1102160
  6. ↑ Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S, Kurth E, Capodieci P, Deplazes-Lauber J, Petropoulos K, Thiel P, Ponsel D, Hee Choi S, LeMotte P, London A, Goetcshkes M, Nolin E, Jones MD, Slocum K, Kluk MJ, Weinstock DM, Christodoulou A, Weinberg O, Jaehrling J, Ettenberg SA, Buckler A, Blacklow SC, Aster JC, Fryer CJ. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene. 2016 May 9. doi: 10.1038/onc.2016.133. PMID:27157619 doi:http://dx.doi.org/10.1038/onc.2016.133
  7. ↑ 7.0 7.1 Aster JC, Pear WS, Blacklow SC. The Varied Roles of Notch in Cancer. Annu Rev Pathol. 2017 Jan 24;12:245-275. doi:, 10.1146/annurev-pathol-052016-100127. Epub 2016 Dec 5. PMID:27959635 doi:http://dx.doi.org/10.1146/annurev-pathol-052016-100127
  8. ↑ Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol. 2012 Jun;23(4):450-7. doi: 10.1016/j.semcdb.2012.01.010., Epub 2012 Jan 28. PMID:22306179 doi:http://dx.doi.org/10.1016/j.semcdb.2012.01.010
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