Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity.

Alterations of various components of the cell cycle regulatory machinery that controls the progression of cells from a quiescent to a growing state contribute to the development of many human cancers. Such alterations include the deregulated expression of G1 cyclins, the loss of function of activities such as those of protein p16INK4a that control G1 cyclin-dependent kinase activity, and the loss of function of the retinoblastoma protein (RB), which is normally regulated by the G1 cyclin-dependent kinases. Various studies have revealed an inverse relationship in the expression of p16INK4a protein and the presence of functional RB in many cell lines. In this study we show that p16INK4a is expressed in cervical cancer cell lines in which the RB gene, Rb, is not functional, either as a consequence of Rb mutation or expression of the human papillomavirus E7 protein. We also demonstrate that p16INK4a levels are increased in primary cells in which RB has been inactivated by DNA tumor virus proteins. Given the role of RB in controlling E2F transcription factor activity, we investigated the role of E2F in controlling p16INK4a expression. We found that E2F1 overexpression leads to an inhibition of cyclin D1-dependent kinase activity and induces the expression of a p16-related transcript. We conclude that the accumulation of G1 cyclin-dependent kinase activity during normal G1 progression leads to E2F accumulation through the inactivation of RB, and that this then leads to the induction of cyclin kinase inhibitor activity and a shutdown of G1 kinase activity.

Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color.

Mutations in the gene encoding the endothelin receptor type B (EDNRB) produce congenital aganglionic megacolon and pigment abnormalities in mice and humans. Here we report a naturally occurring null mutation of the EDNRB gene in spotting lethal (sl) rats, which exhibit aganglionic megacolon associated with white coat color. We found a 301-bp deletion spanning the exon 1-intron 1 junction of the EDNRB gene in sl rats. A restriction fragment length polymorphism caused by this deletion perfectly cosegregates with the sl phenotype. The deletion leads to production of an aberrantly spliced EDNRB mRNA that lacks the coding sequence for the first and second putative transmembrane domains of the G-protein-coupled receptor. Radioligand binding assays revealed undetectable levels of functional EDNRB in tissues from homozygous sl/sl rats. We conclude that EDNRB plays an essential role in the normal development of two neural crest-derived cell lineages, epidermal melanocytes and enteric neurons, in three mammalian species--humans, mice, and rats. The EDNRB-deficient rat may also prove valuable in defining the postnatal physiologic role of this receptor.

Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bc1-2-independent regulator of apoptosis in human B-lineage lymphoma cells.

CD19 receptor is expressed at high levels on human B-lineage lymphoid cells and is physically associated with the Src protooncogene family protein-tyrosine kinase Lyn. Recent studies indicate that the membrane-associated CD19-Lyn receptor-enzyme complex plays a pivotal role for survival and clonogenicity of immature B-cell precursors from acute lymphoblastic leukemia patients, but its significance for mature B-lineage lymphoid cells (e.g., B-lineage lymphoma cells) is unknown. CD19-associated Lyn kinase can be selectively targeted and inhibited with B43-Gen, a CD19 receptor-specific immunoconjugate containing the naturally occurring protein-tyrosine kinase inhibitor genistein (Gen). We now present experimental evidence that targeting the membrane-associated CD19-Lyn complex in vitro with B43-Gen triggers rapid apoptotic cell death in highly radiation-resistant p53-Bax- Ramos-BT B-lineage lymphoma cells expressing high levels of Bcl-2 protein without affecting the Bcl-2 expression level. The therapeutic potential of this membrane-directed apoptosis induction strategy was examined in a scid mouse xenograft model of radiation-resistant high-grade human B-lineage lymphoma. Remarkably, in vivo treatment of scid mice challenged with an invariably fatal number of Ramos-BT cells with B43-Gen at a dose level < 1/10 the maximum tolerated dose resulted in 70% long-term event-free survival. Taken together, these results provide unprecedented evidence that the membrane-associated anti-apoptotic CD19-Lyn complex may be at least as important as Bcl-2/Bax ratio for survival of lymphoma cells.

La costruzione giuridica del modello sociale europeo (con una postilla sul MSE al tempo della crisi globale) [The legal construction of the European social model (with a note on the MSE at the time of the global crisis)]. WP C.S.D.L.E. "Massimo D'Antona" .INT - 88/2011

No abstract.

L’Europa sociale e il diritto: il contributo del metodo comparato [Social Europe and the law: the contribution of the comparative method]. WP C.S.D.L.E. "Massimo D'Antona" .INT - 94/2012

The essay explores the evolution of comparative law and the contribution of its more recent methodological results on the process of European social integration through law. The analysis of the comparative method in general glides on a discipline, such a as labour law, traditionally linked to the "nomos" of the nation state and looks at the process of its own supranationalization through the lens which is the comparative method; a method used mainly by the juridical format (national and supranational courts). The analysis focuses on the fixed term contract and on the vexing question of collective social fundamental rights vis a vis fundamental economic freedoms in the EU where national constitutional traditions and supranational principals risk collision due also to the comparative method.

A B C of gothic architecture /

Includes index.

Sumerian mythology, a study of spiritual and literary achievement in the third millennium, B.C.

Frontispiece accompanied by leaf with descriptive letterpress.

Egypt and Syria under the Circassian sultans, 1382-1468 A.D. : systematic notes to Ibn Taghrî Birdî's chronicles of Egypt /

Mode of access: Internet.

Dedications from the Athenian Akropolis; a catalogue of the inscriptions of the sixth and fifth centuries B. C.

Includes bibliographical references.

The complete confectioner, or, Housekeeper's guide to a simple and speedy method of understanding the whole art of confectionary : the various ways of preserving and candying, dry and liquid, all kinds of fruit, nuts, flowers, herbs, &c. And the method of keeping them fresh and fine all the year round; the different ways of clarifying sugar; with directions for making fruit pastes, bomboons, pastils, compotes, fruit ices, cream ices, marmalades, jellies, jams, cakes, puffs, biscuits, tarts, custards, cheesecakes, sweetmeats, fritters, creams, syllabubs, blanc-mange, flummeries, ornaments for grand entertainments, dragees, syrups of all kinds, nicknacks and trifles for desserts, strong cordials, oils, simple waters, milk punch that will keep 20 years, and all sorts of English wines. Also, the art of making artificial fruit, with the stalks in it, so as to resemble the natural fruit. To which are added, some bills of fare for desserts for private families /

Originally published under title: The compleat confectioner. Cf. Bitting, K.G. Gastronomic bib., p. 190.