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A genome-wide screen was carried out to identify GATA-3 as the most highly enriched transcription factor in the mammary ductal epithelium of pubertal mice and show that GATA-3 is localized to the body cells of terminal end buds (TEBs) and to the mature luminal cells of mammary ducts. The findings suggest that GATA-3 actively maintains luminal epithelial differentiation in the adult mammary gland, which raises important implications for the pathogenesis of breast cancer.

The C-terminal fragment of [Ca.sub.v]1.2, an L-type voltage-gated calcium channel (LTC), associated transcription regulator (CCAT) binds to a nuclear protein, associates with an endogenous promoter and regulates the expression of a wide variety of endogeneous genes important for neuronal signaling and excitability. The results have provided evidence that voltage-gated calcium channels can directly activate transcription and have described a mechanism linking voltage-gated channels to the function and differentiation of excitable cells.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.02.020 Byline: Lorenza Penengo (1), Marina Mapelli (1), Andrea G. Murachelli (1), Stefano Confalonieri (1), Laura Magri (1), Andrea Musacchio (2), Pier Paolo Di Fiore (1)(2)(3), Simona Polo (1)(2), Thomas R. Schneider (1)(2) Abstract: The interaction between ubiquitinated proteins and intracellular proteins harboring ubiquitin binding domains (UBDs) is critical to a multitude of cellular processes. Here, we report that Rabex-5, a guanine nucleotide exchange factor for Rab5, binds to Ub through two independent UBDs. These UBDs determine a number of properties of Rabex-5, including its coupled monoubiquitination and interaction in vivo with ubiquitinated EGFRs. Structural and biochemical characterization of the UBDs of Rabex-5 revealed that one of them (MIU, motif interacting with ubiquitin) binds to Ub with modes superimposable to those of the UIM (ubiquitin-interacting motif):Ub interaction, although in the opposite orientation. The other UBD, RUZ (Rabex-5 ubiquitin binding zinc finger) binds to a surface of Ub centered on Asp58.sub.Ub and distinct from the 'canonical' Ile44.sub.Ub-based surface. The two binding surfaces allow Ub to interact simultaneously with different UBDs, thus opening new perspectives in Ub-mediated signaling. Author Affiliation: (1) IFOM, the FIRC Institute for Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy (2) European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy (3) University of Milan, 20122 Milan, Italy Article History: Received 7 December 2005; Revised 6 February 2006; Accepted 14 February 2006 Article Note: (miscellaneous) Published online: February 16, 2006

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.10.042 Byline: Outi Hallikas (1), Kimmo Palin (2), Natalia Sinjushina (3), Reetta Rautiainen (1), Juha Partanen (3), Esko Ukkonen (2), Jussi Taipale (1) Abstract: Understanding the regulation of human gene expression requires knowledge of the 'second genetic code,' which consists of the binding specificities of transcription factors (TFs) and the combinatorial code by which TF binding sites are assembled to form tissue-specific enhancer elements. Using a novel high-throughput method, we determined the DNA binding specificities of GLIs 1-3, Tcf4, and c-Ets1, which mediate transcriptional responses to the Hedgehog (Hh), Wnt, and Ras/MAPK signaling pathways. To identify mammalian enhancer elements regulated by these pathways on a genomic scale, we developed a computational tool, enhancer element locator (EEL). We show that EEL can be used to identify Hh and Wnt target genes and to predict activated TFs based on changes in gene expression. Predictions validated in transgenic mouse embryos revealed the presence of multiple tissue-specific enhancers in mouse c-Myc and N-Myc genes, which has implications for organ-specific growth control and tumor-type specificity of oncogenes. Author Affiliation: (1) Molecular and Cancer Biology Program, Biomedicum Helsinki, PO Box 63, FIN-00014 University of Helsinki, Finland (2) Department of Computer Science, PO Box 68, FIN-00014 University of Helsinki, Finland (3) Developmental Biology Program, Institute of Biotechnology, PO Box 56, FIN-00014 University of Helsinki, Finland Article History: Received 14 June 2005; Revised 21 September 2005; Accepted 21 October 2005 Article Note: (miscellaneous) Published: January 12, 2006

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.08.012 Byline: Rashu B. Seth, Lijun Sun, Chee-Kwee Ea, Zhijian J. Chen Abstract: Viral infection triggers host innate immune responses through activation of the transcription factors NF-[kappa]B and IRF3, which coordinately regulate the expression of type-I interferons such as interferon-[beta] (IFN-[beta]). Herein, we report the identification of a novel protein termed MAVS (mitochondrial antiviral signaling), which mediates the activation of NF-[kappa]B and IRF3 in response to viral infection. Silencing of MAVS expression through RNA interference abolishes the activation of NF-[kappa]B and IRF3 by viruses, thereby permitting viral replication. Conversely, overexpression of MAVS induces the expression of IFN-[beta] through activation of NF-[kappa]B and IRF3, thus boosting antiviral immunity. Epistasis experiments show that MAVS is required for the phosphorylation of IRF3 and I[kappa]B and functions downstream of RIG-I, an intracellular receptor for viral RNA. MAVS contains an N-terminal CARD-like domain and a C-terminal transmembrane domain, both of which are essential for MAVS signaling. The transmembrane domain targets MAVS to the mitochondria, implicating a new role of mitochondria in innate immunity. Author Affiliation: Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 Article History: Received 8 June 2005; Revised 8 August 2005; Accepted 11 August 2005 Article Note: (miscellaneous) Published online: August 25, 2005