1. Notch1 Transmembrane Receptor Oncogene

2. What is Notch1?  Transmembrane protein involved in a conserved and simple signaling pathway.

3. What is Notch1?  Transmembrane protein involved in a conserved and simple signaling pathway.  Notch1 has 3 domains

4. What is Notch1?  Transmembrane protein involved in a conserved and simple signaling pathway.  Notch 1 has 3 domains  Member of the Notch Family (Notch1-Notch4)

5. What does Notch1 do?  Notch1 plays a role in cell fate determination in many tissues.  e.g. neural and epidermal tissue, hair follicles, dental epithelium.  Essential in T-cell development

6. Notch1 Signaling Pathway  Ligand Binds to Notch1

7. Notch1 Signaling Pathway  Ligand Binds to Notch1  Proteases cleave protein on either side of transmembrane domain

8. Notch1 Signaling Pathway  Ligand Binds to Notch1  Proteases cleave protein on either side of transmembrane domain  Derivative of cytoplasmic domain travels to nucleus as co-activator

9. Notch1 in Model Organisms  First Discovered in neural development in Drosophila  Also found in mice where overexpression and inactivation experiments were carried out

10. Notch1 in Mice  Homozygous Notch1 mutants are embryonic lethal at E10.  They are developmentally delayed.  The thymus, where T-cells are formed, is reduced.

11. Notch1 in Mice  A conditional allele revealed that Notch1 is important at 3 places in Lymphocyte development.

12. Notch1 is an Oncogene  A chromosomal translocation truncates Notch1 and makes it constitutively active.  This allows the cytoplasmic domain to be cleaved without the binding of a ligand.  This leads to uncontrolled expression of Notch target genes.

13. Notch1 is an Oncogene  Notch1 mutations are found in up to 50% of T-cell acute lymphoblastic leukemias (T-ALL).  They are also commonly found in cervical and prostate carcinomas as well as some melanomas.  Some cases of T-ALL have mutations in other Notch family members such as Notch3

14. Possible Breakthroughs  One possible breakthrough is that since the movement of the cytoplasmic domain requires a protease, an inhibitor of this protease could curb constitutive activity.