Aaron Ciechanover, MD, DSc

Ubiquitin-Mediated Proteolysis and Mechanisms of Malignant Transformation

Between the 1950s and 1980s, scientists were focusing their research on how the genome is translated to the proteome, and ignored how proteins are degraded.  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 identification of a multitude of targeted substrates and involved processes, 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 (Figures 1 + 2).

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 the transcriptional activator, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and (ii) evasion of apoptosis. 

(i) 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 agents such as irradiation or chemotherapeutic agents, is a hallmark of malignant cells as their behavior becomes more aggressive.  We are studying the regulation of IAPs (Inhibitors of Apoptosis Proteins), of which many are ubiquitin ligases that inhibit apoptosis by targeting caspases for ubiquitination and degradation.  Not surprisingly, they are aberrantly up-regulated in numerous and diverse malignancies.

Figure 1: The ubiquitin-proteasome system

Ubiquitin is activated by E1 (1) followed by its transfer to an E2 (2). E2 transfers the activated ubiquitin to the substrate that is bound specifically to a unique ligase, E3. Transfer is either direct (3) or via an additional intermediate on the E3 (4, 4a). Successive conjugation of ubiquitin moieties to one another generates a polyubiquitin chain that serves as the degradation signal for the 26S proteasome. The substrate is degraded to peptides (6), and free and reusable ubiquitin is released (7).          

Figure 2: Aberrations in the ubiquitin-proteasome system and pathogenesis of human diseases

Normal degradation of cellular proteins maintains them in a steady state level (upper and lower right side). When degradation is accelerated due an increase in the level of an E3 (Skp2), or expression of a protein that generates a complex with the substrate and targets it for degradation (the Human Papillomavirus E6 oncoprotein that associates with p53 and targets it for degradation), the steady state level of the substrate decreases (upper left side). A mutation in a ligase (such as occurs in Adenomatous Polyposis Coli – APC), or in the substrate's  recognition motif (β-catenin) will result in decreased degradation and accumulation of the substrate. 

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