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Role of Nedd4 family of HECT/WW domain E3 ubiquitin ligases in cell growth and differentiation

Andrea Carrano

Appointment Period: 2002-2003 / Grant Year: [18]

Andrea CarranoTargeting components of the ubiquitin pathways can lead to the development of new therapeutic agents. Because of the wide-ranging roles of the pathway in many cellular processes, it may be difficult to limit the negative effects of inhibitors that target the general ubiquitination machinery. However, inhibitors of ubiquitin ligases will specifically block distinct cellular processes. Our goal is to explore the potential of WWP E3 ligases as novel therapeutic targets in cancer or other diseases.

To identify the cellular pathways in which WWP ligases are involved, I have chosen to collaborate with Dr. Andrew Dillin of the Salk Institute to study the single C. elegans homolog of mammalian WWP proteins, CeWWP. We have been able to show that feeding worms bacteria which express CeWWP dsRNA produces a predominant phenotype of embryonic lethality. The embryonic lethal phenotype we see indicates an essential embryonic function. In addition, we have been able to observe postdevolopmental phenotypes in these worms, including a clear body phenotype which correlates with a reduction of fat in the intestines, as observed by nile red staining. At the present time, we are in the middle of modifier screens using a genome-wide RNAi feeding library to identify genetic interactors of CeWWP. A recessive mutation that can suppress the embryonic lethality/clear phenotype will likely be a mutation in a potential substrate targeted for degradation.

Defects in the function of E3 ligases have been shown to result in a variety of human diseases including cancer, neurodegenerative diseases, and metabolic disorders. Given the role of CeWWP in development and fat metobolism, identification of target molecules of WWP E3 ligases will thus be an important avenue to study.

Carrano AC, Liu Z, Dillin A, Hunter T. A conserved ubiquitination pathway determines longevity in response to diet restriction. Nature. (2009) 460:396-9. PMID: 19553937; PMCID: PMC2746748.