The blood-brain barrier (BBB) provides significant protection against microbial invasion of the brain. However, the BBB is not impenetrable, and mechanisms by which viruses breach it are becoming clearer. In vivo and in vitro model systems are enabling identification of host and viral factors contributing to breakdown of the unique BBB tight junctions. Key mechanisms of tight junction damage from inside and outside cells are disruption of the actin cytoskeleton and matrix metalloproteinase activity, respectively. Viral proteins acting in BBB disruption are described for HIV-1, currently the most studied encephalitic virus; other viruses are also discussed.

The Ets family consists of a large number of evolutionarily conserved transcription factors, many of which have been implicated in tumor progression. Extensive studies on this family of proteins have focused so far mainly on the biochemical properties and cellular functions of individual factors. Since most of the Ets factors can bind to the core consensus DNA sequence GGAA/T in vitro, it has been a challenge to differentiate redundant from specific functions of various Ets proteins in vivo. Recent findings, however, suggest that such apparent redundancy may in fact be a central component of a network of differentially regulated specific Ets factors, resulting in distinct biological and pathological consequences. The programmed "Ets conversion" appears to play a critical role during tumor progression, especially in control of cellular changes during epithelial-mesenchymal transition and metastasis. Coordination of multiple Ets gene functions also mediates interactions between tumor and stromal cells. As such, these new insights may provide a novel view of the Ets gene family as well as a focal point for studying the complex biological control involved in tumor progression. KeywordsEts; transcriptional regulation; ECM; cancer; invasion; metastasis; EMT; epithelium; stroma The Ets family of proteins consists of a large number of evolutionarily conserved transcription factors. There are 25 human and 26 murine Ets family members. Ets factors control specific genes that perform critical roles in diverse processes, including cell proliferation, apoptosis, differentiation, lymphoid cell development, angiogenesis, and invasiveness [Sementchenko and Watson, 2000]. To date, studies in the field have largely focused on individual Ets factors and have indeed yielded valuable, albeit fragmented, information. Recent findings, on the other hand, have suggested that several Ets factors may participate in a coordinated program that modulates cell migration and invasiveness, thus affecting tumor progression toward metastasis. In this review, we will examine the recent progress in Ets biology and provide a forum for discussion on a systemic view of Ets functions. Detailed descriptions of Ets proteins and their functions have been provided in several recent reviews [Watson and Seth, 2000;Watson et al., 2001;Dittmer, 2003;Oikawa and Yamada, 2003].Cancer results from a multi-step series of genetic changes that lead to essential alterations in cell physiology such as loss of growth controls and normal apoptotic response as well as sustained angiogenesis, invasion, and metastasis [Hanahan and Weinberg, 2000]. While it is known that most human tumors are derived from epithelial cells that have undergone multiple genetic alterations [Hanahan and Weinberg, 2000], it is also becoming clear that the alterations

Human nm23 has been implicated in suppression of metastasis in various cancers, but the underlying mechanism of such activity has not been fully understood. Using Drosophila tracheal system as a genetic model, we examined the function of the Drosophila homolog of nm23, the awd gene, in cell migration. We show that loss of Drosophila awd results in dysregulated tracheal cell motility. This phenotype can be suppressed by reducing the dosage of the chemotactic FGF receptor (FGFR) homolog, breathless (btl), indicating that btl and awd are functionally antagonists. In addition, mutants of shi/dynamin show similar tracheal phenotypes as in awd and exacerbate those in awd mutant, suggesting defects in vesicle-mediated turnover of FGFR in the awd mutant. Consistent with this, Btl-GFP chimera expressed from a cognate btl promoter-driven system accumulate at high levels on tracheal cell membrane of awd mutants as well as in awd RNA duplex-treated cultured cells. Thus, we propose that awd regulates tracheal cell motility by modulating the FGFR levels, through a dynamin-mediated pathway.[Keywords: awd/nm23; btl/FGFR; shi/dynamin; tracheal development; Drosophila; cell migration] Supplemental material is available at http://www.genesdev.org.

We show that localized expression of the integrin α 3 protein is regulated at the level of RNA localization by the human homologue of Drosophila Muscleblind, MLP1/MBLL/MBNL2, a unique Cys 3 His zinc-finger protein. This is supported by the following observations: MLP1 knockdown abolishes localization of integrin α 3 to the adhesion complexes; MLP1 is localized in adhesion plaques that contain phospho-focal adhesion kinase; this localization is microtubule-dependent; integrin α 3 transcripts colocalize with MLP1 in distinct cytoplasmic loci; integrin α 3 transcripts are physically associated with MLP1 in cells and MLP1 binds to a specific ACACCC motif in the integrin α 3 3′ untranslated region (UTR) in vitro; and a green fluorescent protein (GFP) open reading frameintegrin α 3 3′ UTR chimeric gene directs GFP protein localization to distinct cytoplasmic loci near the cell periphery, which is dependent on MLP1 and is mediated by the ACACCC motif but is independent of the integrin α 3 signal peptide.We have recently identified a gene that is differentially expressed in many tumours. The cognate protein was named MLP1 for Muscleblind-like protein 1 (GenBank accession #AF491866) because of its high degree of homology with the Drosophila Muscleblind (Mbl) protein. The Drosophila mbl gene is involved in regulatory processes that are associated with the terminal differentiation of photoreceptors and muscles 1,2 . The Mbl protein is characterized by novel Cys 3 His zinc-finger motifs, CX 7 CX 6 CX 3 H-CX 7 CX 4 CX 3 H. Highly conserved homologues of mbl are found from worms and insects to mammals. Three human Mbl-like proteins -named EXP/MBNL1, MBLL/MBNL2 and MBXL/CHCR/MBNL3 -have been partially characterized 3-7 . MLP1 is the same as MBLL/MBNL2 and, as the former name was first used in the GenBank database, we will continue to use it throughout this report for brevity. These three proteins display RNA-binding activity towards transcripts that contain expanded trinucleotide repeats in myotonic dystrophy muscle cells, presumably sequestering the target RNAs 3-5 . These observations, however, did not shed light on the normal cellular functions of this family of proteins, although a role in mRNA processing has been implicated 7 . The developmental functions of Drosophila Mbl do not include early proliferation or differentiation of the muscle precursors 2 . In mbl mutants, muscles detach from the epidermis, indicating a defect in integrin-mediated adhesion. In addition, Mbl protein is found associated with the Zband that is rich in actin. Therefore, these mbl homologues may represent a unique group of regulatory genes that control the cellular functions that are related to cell-matrix interactions and cytoskeletal organization.