Notch: From fly wings to human hematological tumors
| Autor: | Giovanni Palma, Paola Comi, Raffaella Chiaramonte, Katia Rea, Leonardo Mirandola, Sara Larocca |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Notch
medicine.medical_treatment Notch signaling pathway lcsh:RC254-282 Targeted therapy Receptors medicine Proto-Oncogene Proteins c-myc Enzyme Inhibitors Tissue homeostasis biology Intracellular Signaling Peptides and Proteins PTEN Phosp Hematology Precursor Cell Lymphoblastic Leukemia-Lymphoma lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Oncology Notch proteins biology.protein Cancer research Cyclin-dependent kinase 8 Proto-OncogeneProteins c-myc Stem cell Amyloid Precursor Protein Secretases Multiple Myeloma Amyloid precursor protein secretase Proto-Oncogene Proteins c-akt |
| Zdroj: | Archive of Oncology, Vol 17, Iss 3-4, Pp 72-77 (2009) |
| ISSN: | 0354-7310 |
| Popis: | Notch history begins in 1919 with Thomas Hunt Morgan studies on fruit fly mutants. From then, this gene aroused lively interest in the scientific community since it is involved in a wide variety of processes, including morphogenesis, tissue homeostasis, and stem cell maintenance. Deregulation of Notch signaling characterizes several human tumors. Hematopoietic system is affected by mutations of Notch receptors, Notch ligands, and proteins controlling their stability. Approximately 60% T acute lymphoblastic leukemia (T-ALL) patients carry activating Notch1 mutations prompting blasts growth. In addition, multiple myeloma is characterized by Notch signaling hyper-activation due to an abnormal expression of the Jagged2 ligand; this affects not only myeloma cells, but also their interaction with bone marrow microenvironment, influencing tumor burden and bone disease. These findings make Notch a rational target of a therapeutic approach. Inhibitors of the Notch activating enzyme, ?-Secretase, have been successfully used in vitro and in vivo and are currently under clinical trials for T-ALL and breast cancer. Yet a wide use of these inhibitors is prevented by frequently occurring drug resistance. To elucidate the mechanism underlying this phenomenon, a number of pathways have been identified mediating Notch biological effects: AKT and c-Myc are frequently deregulated in leukemic patients and account for resistance to ?-Secretase inhibitors by acting downstream Notch receptor. Therefore, the interaction of Notch with other cancer-associated proteins should be clarified to predict the biological outcome of a Notch targeted therapy and possibly, to exploit combined treatments against the key deregulated elements in Notch-associated cancers. |
| Databáze: | OpenAIRE |
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