The Human Papillomavirus E6 protein and its contribution to malignant progression

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E3-Ubiquitin Ligase/E6-AP Links Multicopy Maintenance Protein 7 to the Ubiquitination Pathway by a Novel Motif, the L2G Box

Ubiquitin ligases are generally assumed to play a major role in substrate recognition and thus provide specificity to a particular ubiquitin modification system. The multicopy maintenance protein (Mcm) 7 subunit of the replication licensing factor-M was identified as a substrate of the E3-ubiquitin ligase/E6-AP by its interaction with human papillomavirus-18E6. Mcm7 is ubiquitinated in vivo in both an E6-AP-dependent and -independent manner. E6-AP functions in these reactions independently of the viral oncogene E6. We show that recognition of Mcm7 by E6-AP is mediated by a homotypic interaction motif present in both proteins, called the L2G box. These findings served as the basis for the definition of substrate specificity for E6-AP. A small cluster of proteins whose function is intimately associated with the control of cell growth and/or proliferation contains the L2G box and is thereby implicated in an E6-AP and, by default, HPV-E6-dependent ubiquitination pathway

Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the β-TrCP ubiquitin ligase receptor

The discs large (hDlg) tumor suppressor is intimately involved in the control of cell contact, polarity, and proliferation by interacting with several components of the epithelial junctional complex and with the APC tumor suppressor protein. In epithelial cells, hDlg protein stability is regulated through the ubiquitin-proteasome pathway: hDlg is actively degraded in isolated cells, whereas it accumulates upon cell-cell contact. During neoplastic transformation of epithelial cells, loss of the differentiated morphology and progression toward a metastatic phenotype correlate with down-regulation of hDlg levels and loss of contact-dependent stabilization. Here we show that upon hyperphosphorylation, hDlg interacts with the beta-TrCP ubiquitin ligase receptor through a DSGLPS motif within its Src homology 3 domain. As a consequence, overexpression of beta-TrCP enhances ubiquitination of Dlg protein and decreases its stability, whereas a dominant negative beta-TrCP mutant inhibits this process. Furthermore, a mutant Dlg protein that is unable to bind beta-TrCP displays a higher protein stability and is insensitive to beta-TrCP. Using RNA interference, we also demonstrate that endogenous beta-TrCP regulates hDlg protein levels in epithelial cells. Finally, we show that beta-TrCP selectively induces the degradation of the membrane-cytoplasmic pool, without affecting the nuclear pool of hDlg

A Class of Cosmological Matrix Models

We discuss a class of matrix models describing cosmology with a light-like singularity, generalizing the model proposed by Craps et al. in hep-th/0506180.Comment: 12 pages, harvmac, v2: final version published in Phys. Lett.

Risk of radiation exposure from the Transportation of high-level nuclear waste

Transportation of high-level nuclear waste poses a potential risk of exposure from radiation to people of Las Vegas and the surrounding environment. 77,000 metric tons of waste is scheduled to start arriving at Yucca Mountain in 2010. For 24 years legal weight trucks will transport high-level nuclear waste through 109 cities with populations over 100,000. The population of Las Vegas is over 400,000 people. In all, legal weight trucks will cross 43 states traveling millions of highway miles (see appendix B). The U. S. Department of Energy estimates expected radiological risk from accidents would be no higher than 0.003 latent cancer fatalities in Clark County. In its analysis state specific data was used in RADTRAN to estimate transport risk to Nevada. The study looked at how route specific data has been applied in other studies using RADTRAN. A Lincoln County case study suggest national and state data underestimates risk of transportation of high-level nuclear waste

Comparison of p53 and the PDZ domain containing protein MAGI-3 regulation by the E6 protein from high-risk human papillomaviruses

Central to cellular transformation caused by human papillomaviruses (HPVs) is the ability of E6 proteins to target cellular p53 and proteins containing PDZ domains, including MAGI-3, for degradation. The aim of this study was to compare E6-mediated degradation of p53 and MAGI-3 under parallel experimental conditions and further with respect to the involvement of proteasomes and ubiquitination. We also compared the degradation of p53 and MAGI-3 by E6 from several HPV types including different variants from HPV-33. All of the E6 genes from different HPV types displayed similar abilities to mediate the degradation of both p53 and MAGI-3 although there may be subtle differences observed with the different 33E6 variants. There were however differences in E6 mediated degradation of p53 and MAGI-3. Proteasome inhibition assays partially protected p53 from E6 mediated degradation, but did not protect MAGI-3. In addition, under conditions where p53 was ubiquitinated by E6 and MDM2 in vivo, ubiquitination of MAGI-3 was not detected. These results imply that although both p53 and MAGI-3 represent effective targets for oncogenic E6, the mechanisms by which E6 mediates p53 and MAGI-3 degradation are distinct with respect to the involvement of ubiquitination prior to proteasomal degradation

DLG1 (discs, large homolog 1 (Drosophila))

The human homologue of Drosophila disc large tumor suppressor protein (hDlg) also known as synapse-associated protein 97, is a scaffold protein, a member of the membrane-associated guanylate kinase family. It is one of the proteins known to act cooperatively in regulating cell polarity and proliferation, suggesting an important connection between epithelial organization and cellular growth control. An abnormal expression of hDlg has been reported in several cancer types.This protein may have a role in cell junction formation, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation