When viral oncoprotein meets tumor suppressor: A structural view

Wistar Institute and Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genes & Development (Impact Factor: 10.8). 10/2006; 20(17):2332-7. DOI: 10.1101/gad.1471706
Source: PubMed
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    • "These regions are parts of the human papillomavirus E7 (HPV-E7), Adenovirus E1A (Ad-E1A), and Simian virus 40 large T antigen (SV40-LTa) oncoproteins [(Chellappan et al., 1992; Nevins, 1992) and the reviews (Lee and Cho, 2002; Helt and Galloway, 2003; Felsani et al., 2006)]. These structures shed light on the mechanisms used by these viral factors, which clearly depend on their capabilities in binding pRb, to release E2F and thus activate the E2F transcriptionally regulated genes into the S-phase of the cell cycle (Liu and Marmorstein, 2006). Multiple sequence alignment of the pocket domain of pRb homologues, and the residues of the pRb pocket domain that are involved in the interaction with the regions of HPV-E7, Ad-E1A, and SV40-LTa viral factors from the protein data bank (PDB) structures available are shown in Figure 2. Ad-E1A, HPV-E7, and SV40-LTa share a conserved LxCxE motif capable of high-affinity binding to the pocket domain of pRb, but which is not sufficient alone for the inactivation of pRb (Raychaudhuri et al., 1991; Patrick et al., 1994; Zalvide et al., 1998). "
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    ABSTRACT: The Retinoblastoma (RB) family consists of three genes, RB1, RBL1 and RBL2, that code for the pRb, p107 and pRb2/p130 proteins, respectively. All these factors have pivotal roles in controlling fundamental cellular mechanisms such as cell cycle, differentiation and apoptosis. The founder and the most investigated RB family protein is pRb, which is considered to be the paradigm of tumor suppressors. However, p107 and pRb2/p130 clearly display a high degree of structural and functional homology with pRb. Interestingly, these factors were first identified as physical targets of the Adenovirus E1A oncoprotein. Indeed, RB family proteins are the most important and widely investigated targets of small DNA virus oncoproteins, such as Adenovirus E1A, Human Papillomavirus E7 and Simian Virus 40 large T antigen. By interacting with pRb and with other RB family members, these oncoproteins neutralize their growth suppressive properties, thus stimulating proliferation of the infected cells, de-differentiation and resistance to apoptosis. All these acquired features strongly favor the rise and selection of immortalized and mutation-prone cells, leading to a higher propensity in undergoing transformation. Our present work aims to illustrate and delve into these protein- protein interactions. Considering that these viral oncoproteins are dispensable for normal cellular functions, they can create "oncogene addiction" in the infected/transformed cells. This makes the possibility to dismantle these interactions extremely attractive, thus promoting the development of highly specific smart molecules capable of targeting only the infected/transformed cells that express these viral factors. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 02/2013; 228(2). DOI:10.1002/jcp.24137 · 3.84 Impact Factor
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    • "The structure of the pRb pocket domain bound to a LxCxE-containing peptide from HPV-E7 reveals that the LxCxE sequence binds within a shallow groove on the B domain of the pocket (Lee et al. 1998). Biochemical and structural studies suggest that while conserved region 3 (CR3) of HPV-E7 competes for a portion of the pRb Cterminal region that partially overlaps with one of the bipartite binding sites for the E2F/DP heterodimer, leading to E2F displacement (Kim et al. 2001; Rubin et al. 2005; Liu et al. 2006), the LTa of SV40 uses an ATPdependent molecular chaperon mechanism to dissemble pRb/E2F complexes (Kim et al. 2001). Adenovirus E1A appears to disrupt pRb/E2F complexes through a mechanism that differs from HPV-E7 and SV40-LTa. "
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    ABSTRACT: The adenovirus (Ad) E1A (Ad-E1A) oncoprotein mediates cell transformation, in part, by displacing E2F transcription factors from the retinoblastoma protein (pRb) tumor suppressor. In this study we determined the crystal structure of the pRb pocket domain in complex with conserved region 1 (CR1) of Ad5-E1A. The structure and accompanying biochemical studies reveal that E1A-CR1 binds at the interface of the A and B cyclin folds of the pRb pocket domain, and that both E1A-CR1 and the E2F transactivation domain use similar conserved nonpolar residues to engage overlapping sites on pRb, implicating a novel molecular mechanism for pRb inactivation by a viral oncoprotein.
    Genes & Development 12/2007; 21(21):2711-6. DOI:10.1101/gad.1590607 · 10.80 Impact Factor
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    ABSTRACT: BKV is a human polyomavirus that establishes a lifelong, persistent infection of the urinary tract. The virus encodes oncoproteins that induce tumors in animal models, and BKV DNA has been detected in human urinary tract tumors, including prostate. Prostate tumors have a relatively low frequency of mutations in the p53 and Rb1 genes, indicating that an agent such as a Virus may be inactivating their functions. The aims of this proposal are to determine if BKV is present in prostate tumors and, if so, whether viral oncogenes are expressed. To accomplish this, normal and tumor tissue from individual patients will be analyzed. PCR, in situ PCR, and in situ hybridization will be performed to determine the presence of viral sequences, and RT-PCR and immunohistochemistry will be used to examine gene expression. Viral sequences from patients will be cloned and their function compared to wild type virus. This past year, we optimized most of these assays and began to analyze samples. We detect the presence and expression of the virus in a subset of normal and cancer cells. At this time, firm conclusions cannot be drawn as more samples need to be analyzed. If BKV is associated with some prostate cancers, our knowledge of the virus will be useful in designing drugs and vaccines for treatment.
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