Deregulation of the Ubiquitin Ligase Subunit Skp2 in Breast Cancer

摘要

Over-activation of positive cell cycle regulators and inactivation of cyclin-dependent kinase inhibitors (ckis) play a significant role in oncogenesis. We have shown previously that the cki p27 is a substrate of the ubiquitin-dependent proteolytic pathway. Importantly, we have found that aggressive human carcinomas contain high p27-specific proteolytic activity and that the absence of p27 is a powerful prognostic marker for poor survival in patients with breast carcinomas. These data suggest that aggressive tumors may obtain a growth advantage by selecting clone(s) that express low p27 because of an increase in its degradation. Our initial concept is that specific ubiquitinylating enzymes responsible for recognizing and driving these proteins into the proteolytic pathway may themselves be targets of oncogenic events. This would consequently affect the timed-degradation and the cellular abundance of their substrates. If our predictions are correct, ubiquitinylating enzymes might turn out to be important prognostic markers in human cancer and, hopefully, novel therapeutic targets. We have found that the F-box protein Skp2 is a rate- limiting component of the machinery that ubiquitinylates and degrades p27. The goal of this project is to study the signals regulating Skp2 activity in breast epithelium and how these events are deregulated in breast cancer cells.