Abstract
The importance of ubiquitin and ubiquitin-like proteins in physiology and medicine has evolved tremendously during the past 2 decades largely due to the exponential accumulation of evidence supporting a paramount role of these proteins in the regulation of various biological and pathological phenomena. Accordingly, numerous studies have increased our understanding of the role of protein modification via ubiquitin or ubiquitin-like proteins in cancer during the past several years. Given these remarkable developments along with a practical need for identification of novel targets for anticancer therapy, there is a necessity for a fresh synthetic view at the ubiquitin-dependent mechanisms that play an important role in human oncological diseases. This review issue addresses this pressing need by bringing together articles from leading groups in the field.
One of the key questions to understanding the role of ubiquitination-dependent mechanisms of cell transformation lies within tumor cells themselves. Given that an increased rate of protein synthesis is often required to support the transforming events and can contribute to the mechanisms of tumor progression, the role of the translation and protein quality control processes becomes paramount. Shcherbik and Pestov discuss the role of ubiquitin and ubiquitin-like molecules in ribosome biogenesis and how ribosome stress modulates the ubiquitin ligase activity of MDM2 and p53 regulation.
Of the enzymes regulating ubiquitin conjugation, it is the E3 ligase that typically provides substrate selectivity. The largest family of E3 ligases is the Cullin-based Ring ligase CRL. This is a multi-subunit protein complex in which one protein subunit provides substrate-specific recognition (an adaptor) but has no intrinsic activity for the transfer of ubiquitin. Hence, this adaptor must be scaffolded to yet another protein harboring this ubiquitinating activity. The scaffolding function is carried out by a family of proteins referred to as Cullins. The review by Lee and Zhou provides insights into our understanding of the functional relationship between the Cullin family of proteins and neoplastic growth. The enzymatic activity of the CRLs is provided by 1 of 2 small Ring finger–containing proteins: RBX1 and RBX2. Wei and Sun describe our current understanding of the functions of these small Ring finger–containing proteins. Soucy and colleagues review how the ubiquitin ligase activity of CRLs is regulated by the covalent attachment of the ubiquitin-like molecule Nedd8 and the potential use of a Nedd8-activating enzyme inhibitor for cancer therapy.
The proper temporal control of cell cycle transitions is central to normal cell division. Alterations in the accumulation and, hence, activation of cyclin-dependent kinases directly contribute to neoplastic growth. This is particularly evident when considering growth factor–dependent G1 phase progression. Deregulation of G1 phase regulation is a common feature of essentially all cancers. While transcription and translation are inherently necessary processes, it is protein degradation that provides the switch-like activity that rapidly and irreversibly shuts off key regulatory proteins. During the past decade, significant progress has been made in deciphering the role of ubiquitin-dependent proteolysis for cell division. The review by Diehl and Bhaskar provides an overview of the role of E3 ubiquitin ligases in G1 to S phase progression.
Almost any change in cellular homeostasis that results from exogenous stimuli will initiate a complex cascade of inducible enzymes and related transcription factors in an attempt to return the cell to its original equilibrium. It is, however, the type and the level of specific cell surface signaling receptors that dictate the nature and the extent of these cellular responses. HuangFu and Fuchs review the latest development in ubiquitination-dependent regulation of these receptors and their role in cancers.
The paramount importance of inflammation in cancer prompts a renewed interest in the mechanisms of action underlying the effects of proinflammatory cytokines and signaling pathways elicited by these cytokines. Activation of the nuclear factor kappaB (NF-κB) pathway has been long viewed as a key characteristic of the malignant transformation, tumor development, progression, metastases, and an important mechanism in tumor protection against anticancer therapeutics. Whereas a central role of both proteolytic-targeting and nonproteolytic protein ubiquitination in NF-κB activation was demonstrated almost 15 years ago, we are only now beginning to appreciate the true complexity of these regulatory events. An avalanche of data obtained in various experimental systems has contributed to diverse and sometimes opposing conclusions that breed controversies and ultimately preclude efficient targeting of specific elements within this signaling pathway for therapeutic purposes. A review by Habelhah takes a fresh look at the state of ubiquitin-dependent mechanisms in NF-κB activation.
Ubiquitin-like protein SUMO (codiscovered as an apoptotic regulator Sentrin) tags predominantly nuclear proteins and plays an important role in numerous cellular functions. Cell-autonomous SUMO-dependent processes have been long implicated in human cancers. However, in recent years, novel understanding for the role of SUMOylation/de-SUMOylation in vascular networks that feed cancer cells has been discovered along with the importance of these mechanisms for tumor progression. A synthetic view at the alterations of cellular mechanisms controlled by SUMO and its overall importance for tumorigenesis as well as potential therapeutic implications are highlighted by Bawa-Khalfe and Yeh in this issue.
The AAA ATPase p97 (called Cdc48p in yeast) is emerging as an important player in many ubiquitin-dependent processes. This essential and highly conserved protein represents 1% of the total protein in the eukaryotic cell and is targeted to substrates by a growing number of adaptor proteins. We have only begun to appreciate the importance of p97-containing complexes and still know very little about their biochemical, cellular, and molecular activities. Dale Haines reviews p97’s functions and the emerging evidence for p97 and p97 adaptors in tumorigenesis. The importance of ubiquitination in the endoplasmic reticulum–associated degradation (ERAD) and alterations of this regulation during chronic ER stress in cancer is analyzed by Tsai and Weissman. Tso-Pan Yao summarizes the mechanistic role that ubiquitination plays in the clearance of potentially toxic protein aggregates by the aggresome-autophagy pathway and the possibility of targeting this pathway for cancer therapy.
Our expanding knowledge of how cells respond to DNA damage has revealed multiple roles for protein modification, with protein ubiquitination/SUMOylation being highly prevalent. Following DNA damage, many proteins are ubiquitinated, resulting in their destruction, and this is generally an important feature of cell adaptation to this stress. However, these modifications are not solely in place to regulate protein destruction. Rather, ubiquitin or SUMO modification of key checkpoint signaling proteins and of histones surrounding DNA breaks provides critical amplification signals essential to initiate cell adaptation. In their review, Tang and Greenberg discuss how such protein modifications contribute to chromatin organization around a double-strand break and thus to cell fate decisions.
Collectively, work during the past several years has contributed to an increased appreciation for the ever-expanding role of ubiquitin- and ubiquitin-like protein modification in the regulation of both normal and neoplastic cell growth. Given this trend, the next decade promises to be equally (if not more) exciting as it should not only deepen our theoretical understanding and resolve the controversies but also evolve toward more translational efforts that exploit ubiquitin-related targets for the anticancer therapies.