Intracellular protein degradation and mechanisms of cancer
Between the 1950s and 1980s, scientists were focusing on how the genome is translated to transcriptome and then to the proteome, but how proteins are degraded has remained a neglected research area. The discovery of the ubiquitin-proteasome system (UPS) with its numerous functions has changed the paradigm that regulation of cellular processes occurs mostly at the transcriptional and translational levels, and has set regulated proteolysis in a prominent position. With the multitude of substrates targeted and processes involved, it is not surprising that aberrations in the pathway have been implicated in the pathogenesis of many diseases, among them certain malignancies and neurodegenerative disorders. Consequently, the system has become a platform for drug targeting, and one successful anti-cancer drug is already on the market.
One main focus of research in our laboratory is the involvement of the UPS in the pathogenesis of malignant transformation. Within this enormously complex process, we are studying two different pathways: (i) activation of NF-κB, and (ii) evasion of apoptosis.
(i) The transcriptional activator NF-κB is a strong anti-apoptotic factor and is constitutively up-regulated in many malignancies. Since NF-κB is activated by the UPS, we are using molecular, biochemical, and cell biological approaches to study the underlying normal and malignancy-induced aberration(s) involved.
(ii) Evasion of apoptosis or gradual development of resistance to genotoxic stimuli, such as irradiation or chemotherapy, is a hallmark of malignant cells as their behavior becomes more aggressive. We are studying the regulation of IAPs - Inhibitors of Apoptosis Proteins, many of them are ubiquitin ligases that inhibit apoptosis by targeting caspases for ubiquitination and degradation. Not surprisingly, they are aberrantly up-regulated in numerous malignancies.