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The critical protein interactions and structures that elicit growth deregulation in cancer and viral replication

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One of the greatest challenges in biomedicine is to define the critical targets and network interactions that are subverted to elicit growth deregulation in human cells. Understanding and developing rational treatments for cancer requires a definition of the key molecular targets and how they interact to elicit the complex growth deregulation phenotype. Viral proteins provide discerning and powerful probes to understand both how cells work and how they can be manipulated using a minimal number of components. The small DNA viruses have evolved to target inherent weaknesses in cellular protein interaction networks to hijack the cellular DNA and protein replication machinery. In the battle to escape the inevitability of senescence and programmed cell death, cancers have converged on similar mechanisms, through the acquisition and selection of somatic mutations that drive unchecked cellular replication in tumors. Understanding the dynamic mechanisms through which a minimal number of viral proteins promote host cells to undergo unscheduled and pathological replication is a powerful strategy to identify critical targets that are also disrupted in cancer. Viruses can therefore be used as tools to probe the system‐wide protein‐protein interactions and structures that drive growth deregulation in human cells. Ultimately this can provide a path for developing system context‐dependent therapeutics. This review will describe ongoing experimental approaches using viruses to study pathways deregulated in cancer, with a particular focus on viral cellular protein‐protein interactions and structures. WIREs Syst Biol Med 2011 3 48–73 DOI: 10.1002/wsbm.88

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Figure 1.

Exploiting the convergence between DNA viruses and tumor mutations to define the critical protein structures and interactions that elicit the complex growth deregulation phenotype. Cancer is a complex phenotype at the ‘top’ that is driven by the acquisition of a myriad of genome mutations at the ‘bottom’. Unfortunately, we have a poor understanding of the protein structures and interactions in higher‐order networks that are disrupted by gene mutations to elicit growth deregulation. There is a profound overlap between the cellular targets of small DNA virus proteins and tumor mutations. Evolution has selected for a minimal number of viral proteins that target the critical protein interaction hubs (red dots) that regulate cellular DNA replication and survival. Thus, viral proteins are powerful tools with which to define the organization and function of cellular protein networks that regulate replication and survival. It is this fertile ‘middle’ ground that provides novel and promising opportunities for therapeutic intervention.

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Figure 2.

Adenovirus protein interactions target critical cellular hubs to elicit growth deregulation in quiescent human epithelial cells. Adenovirus early proteins (only some of which are shown) act together as a program to target critical cellular hubs that regulate replication and survival in human cells. Many of the same cellular proteins and networks of interactions are also disrupted by tumor mutations.

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Figure 3.

Viral proteins use molecular mimicry and intrinsic disordered regions to dominate and usurp cellular protein–protein interactions. (a) A smaller viral protein can dominate and out‐compete endogenous cellular protein interactions by using a larger complementary interaction surface that has higher affinity. For example, SV40 LT uses a larger protein interface to out‐compete DNA in binding to p53. (b) Cellular proteins with intrinsic disordered regions exhibit a rapid equilibrium between different conformational states (through folding and unfolding), but adopt a single conformation upon binding to a cognate interaction partner. This allows cellular ‘hub’ proteins to use the same region to interact with multiple and often disparate partners. Such interactions are characterized as having high specificity but low affinity. Viral proteins also use intrinsic disordered regions to interact with different cellular proteins. However, by using a larger disordered region and complementary interaction surface they can bind to target proteins with a higher affinity than endogenous interactions. One example of this is adenovirus E1A, which out‐competes p53 and other cellular proteins to interact with CBP, as discussed in the main text. Both modes of binding can result in the displacement of cognate cellular interacting proteins, which are then available to participate in alternate protein complexes. This also has important consequences in considering how protein interaction complexes targeted by viral proteins and tumor mutations affect system‐wide protein interaction networks to elicit growth deregulation.

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Figure 4.

Exploiting viruses as a powerful and simple experimental platform for an integrative system in understanding of human growth deregulation. (a) As discussed in the text, defining the interactions and structures of DNA virus proteins systematically can reveal the critical protein networks that regulate cellular growth and survival. (b) This knowledge can be exploited to identify key interactions that are also targeted by tumor mutations and for the development of novel therapies. (c) Furthermore, the cellular protein interaction networks disrupted by viral proteins can be integrated with quantitative measurements of the global transcriptional, translational, and proteomic changes that elicit growth deregulation in the dynamics of infection in quiescent human primary cells. Using simple viral genetics, RNAi and chemical genetics, the critical proteins interactions that elicit growth deregulation can be systematically defined. Together, this provides a powerful platform to approach an integrative understanding of growth deregulation, and which could be used to predict and test rational combination therapies.

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Blanche Capel

Blanche Capel

earned her Ph.D. at the University of Pennsylvania and has been at Duke University since 1993. She earned her endowed professorship, the James B. Duke Professor of Cell Biology, for the meaningful discoveries she has made since her postdoctoral work in genetics at the National Institute for Medical Research in London. The broad goal of the research in Dr. Capel’s laboratory is to characterize the cellular and molecular basis of morphogenesis – how the body forms. She uses gonadal (gender/sex) development in the mouse as her model system and investigates a gene she helped discover, Sry, the male sex determining gene. Gonad development is unique in that a single rudimentary tissue can be induced to form one of two different organs, an ovary or testis, and she is learning all she can about this central mystery of biology.

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