The role of the c-Jun ubiquitin ligase Fbw7 in the nervous system.

Fbw7 belongs to the family of F-box proteins, which function as substrate recognition subunits of SCF complexes. Fbw7 controls the stability of several proteins including cyclin E, the Notch intracellular domain and c-Myc. In 2004 our lab additionally identified phospho-c-Jun as an Fbw7 substrate, c-Jun is part of the AP-1 transcription complex, whose activity is strongly induced in response to numerous signals such as growth factors, cytokines and extracellular stresses. Furthermore elevated phospho-c-Jun levels induce neuronal apoptosis. To investigate the significance of c-Jun regulation by Fbw7 in the nervous system, I generated mice harbouring a floxed fbw7 allele, fbw7. fbw7 mice were bred to various Cre transgenic lines that express the Cre recombinase under nervous system specific promoters to obtain mice with a tissue specific deletion of Fbw7. I confirmed published results that ubiquitous deletion of Fbw7 mediated by PGK-Cre is lethal. To delete Fbw7 at the stage of neuronal precursors, fbwff mice were crossed to the Nestin-cre line (fbw7). These mice die perinatally and show an increase in apoptosis at El6. As the lethality of the fbw7AN mice does not allow the investigation of Fbw7 in the adult nervous system, further crosses, using other cre-transgenic lines, were set up. Fbw7 deletion in postmitotic neurons (fbw7ApN) causes a Parkinson's disease like phenotype with a severe hindlimb tremor and a reduced cortical cellularity. Fbw7 deletion in the cerebellar vermis (fbw7ACb) resulted in cerebella that are characterised by a reduced size, foliation defects accompanied by an astrocytic gliosis and a phospho-c-Jun dependent Purkinje cell loss. Concomitant deletion of c-Jun in the cerebellum (fbw7ACb :c-junACb) partially rescues the cerebellar phenotype caused by Fbw7 deletion. Thus the data in this thesis demonstrate a role for Fbw7 in cerebellar development and the central nervous system and identify c-Jun as an essential Fbw7 substrate in the nervous system

Myc proteins in brain tumor development and maintenance

Myc proteins are often deregulated in human brain tumors, especially in embryonal tumors that affect children. Many observations have shown how alterations of these pleiotropic Myc transcription factors provide initiation, maintenance, or progression of tumors. This review will focus on the role of Myc family members (particularly c-myc and Mycn) in tumors like medulloblastoma and glioma and will further discuss how to target stabilization of these proteins for future brain tumor therapies

F-box and WD repeat domain-containing 7 regulates intestinal cell lineage commitment and is a haploinsufficient tumor suppressor.

BACKGROUND and AIMS: The E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (Fbw7) degrades several proto-oncogenes including c-Myc, cyclinE, Notch1, and c-Jun. Fbw7 is the fourth most frequently mutated gene in human colorectal carcinomas and has recently been described as a poor prognosis marker in human colorectal carcinoma; however, the molecular mechanism underlying fbw7 mutations in intestinal tumor suppression is unclear. METHODS: To address the role of fbw7 in intestinal homeostasis and tumorigenesis, we generated conditional knock-out mice lacking fbw7 in the intestine and evaluated the effect of fbw7 absence in normal intestinal homeostasis and in adenomatous polyposis coli-mediated tumorigenesis. In parallel, we analyzed a cohort of human tumors bearing mutations in fbw7. RESULTS: Fbw7 was found to be highly expressed in the transit-amplifying progenitor cell compartment, and its deletion resulted in impaired goblet cell differentiation and accumulation of highly proliferating progenitor cells. This function of Fbw7 was mirrored during tumor formation because absence of Fbw7 increased proliferation and decreased differentiation of tumors triggered by aberrant Wnt signalling. Fbw7 exhibited haploinsufficiency for intestinal tumor suppression. Biallelic fbw7 inactivation increased cellular proliferation in physiologic and pathologic conditions in a c-Jun-dependent manner. Increased Notch activity was also observed in human tumors carrying heterozygous fbw7 mutations, suggesting that fbw7 haploinsufficiency for antagonizing Notch activity is conserved between human and murine cancers. CONCLUSIONS: Fbw7 regulates intestinal biology and tumorigenesis by controlling the abundance of different substrates in a dose-dependent fashion, providing a molecular explanation for the heterozygous mutations of fbw7 observed in human colorectal carcinoma

Polarized electroluminescence in double layer LEDs with perpendicularly oriented polymers

Polarized light over a large spectral region is provided by the novel procedure described in this work. The active material of these light-emitting diodes (LEDs) is formed by two polymer layers that are oriented perpendicularly to each other. The orientation is obtained using the rubbing technique combined with thermal annealing The Figure represents the electroluminescence (EL) emission from the two-layer LED and its structure (see also inside front cover)

Polarized electroluminescence from double-layer LEDs with active film formed by two perpendicularly oriented polymers. Chromogenic Phenomena in Polymers

The aim of this work is to study the feasibility of a double layer device, where the two active materials are formed, respectively, by two oriented polymers, whose orientation direction is orthogonal, and which can emit simultaneously in different regions of the visible spectrum. We demonstrate that the anisotropy of the polymers is not lost when they are perpendicularly oriented, obtaining polarized light in a large spectral region, extending from the green to the red. The emitted light, observed through a polarizer, can be varied from green to red by simply rotating the polarization axis, obtaining polarized light of variable colour. This peculiar device design is particularly appealing as it can increase the versatility of organic LEDs providing polarized light with easily variable colour emission