MGH EIF 2005 · Regulation of Apoptosis through Ubiquitylation - The Role of the E3 Ubiquitin Ligase Activity of Inhibitor of APoptosis Proteins (IAPs) in Apoptosis

Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.

Накратко на български

Цел на проекта

The co-ordination and balance between cell proliferation and cell death is crucial for normal development of multicellular organisms as well as tissue-size homeostasis in the adult. Cancer occurs when this delicate balance is disrupted by mutations allowing the cell to proliferate and survive inappropriately.Certain members of the Inhibitor of Apoptosis proteins (IAPs) protein family play a pivotal role in regulating caspase activation and activity. IAPs are evolutionarily conserved from insects to humans and suppress apoptosis induced by a large variety of cell death triggers. It is now clear that several human IAP homologues are deregulated in cancers, suggesting that IAP-mediated suppression of apoptosis contributes to tumour pathogenesis, progression, and resistance to drug treatment.The mechanism of apoptosis is remarkably conserved, although with the expected greater complexity in mammals. In Drosophila cell survival is ensured by the IAP, DIAP1. Molecular and genetic data indicate that DIAP1 utilizes two independent mechanisms to regulate apoptosis. One relies upon the E3 ubiquitin protein ligase activity of DIAP1¿s own RING-finger while the other, the N-end rule, functions independently of this domain.Despite that most IAPs identified in humans also contain a RING-finger motif and display E3 ubiquitin protein ligase activity, only little is known about how this activity of IAPs regulates apoptosis. The objective of the proposed research is to study the molecular mechanisms through which the ubiquitin system impacts on caspase regulation with specific focus on the role for IAP proteins. I will initially investigate how DIAP1 neutralizes effector caspases via the N-end rule mediated degradative pathway.Moreover, I will study the importance of DIAP1¿s own E3 ubiquitin protein ligase activity in regulating apoptosis. Finally, I will expand my study to human IAPs and test whether my findings from Drosophila are evolutionarily conserved in humans.

Оригинален текст от CORDIS (на английски).

Участници

• THE BREAKTHROUGH TOBY ROBINS BREAST CANCER RESEARCH CENTREКоординаторНиво градОбединеното кралство

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