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The E1A gene of adenovirus 5 carries out a number of functions in infection and oncogenic transformation, including the transcriptional activation of viral and cellular genes, the repression of transcriptional enhancers, and cooperation with the adenovirus E1B gene or with the ras oncegene to transform primary cells. The purpose of this work was to investigate the mechanism of action of E1A, by determining the regions of the proteins that are required for these functions. Deletion and point mutations were made in the region unique to the larger E1A mRNA, by exonuclease digestion and deletion loop mutagenesis respectively. These mutants and a series of mutants which delete sequences spanning the entire coding region, were examined for their effect on transcriptional activation, enhancer repression, and transformation. The region which, when deleted, rendered E1A defective for transcriptional activation was found to be confined to the region unique to the 13s mRNA and the beginning of exon 2. Mutations in three regions, all within the 12s exon 1, affected repression activity. The first two, the N terminal region of the protein, and a region, CR1, conserved between adenovirus serotypes, were essential for repression activity. The third region, at the end of exon 1 of the 12s mRNA, was probably only indirectly involved in repression. Deletions in three regions of exon 1 resulted in a loss of the transforming function of E1A. The first two corresponded to the regions required for repression, suggesting that enhancer repression is a component of transformation. The third region, containing CR2, also conserved between adenovirus serotypes, is functionally distinct from the other two and appeared to affect the morphology of the transformants. These two functions did not operate efficiently when present ion separate plasmids. The 13s unique region and exon 2 were not required for transformation but the loss of the transactivation function of E1A did result in an increased adhesiveness of the transformants. / Thesis / Doctor of Philosophy (PhD)

This paper analyzes the utilization of repression and democratic institutions by a non-democratic government striving for political power and private rents. We find that economic development has different impacts on policy choices, depending on whether it appears in the form of rises in income or in education: A higher income level reduces democracy, whereas more education leads to both more democracy and more repression. These theoretical findings are corroborated by panel data regressions.

La cathepsine D est une aspartyl protéase lysosomale surexprimée et hypersécrétée par les cellules épithéliales cancéreuses mammaires. C'est un marqueur de mauvais pronostic du cancer du sein. Elle stimule la prolifération des cellules cancéreuses, la croissance invasive des fibroblastes et la formation des métastases. Les travaux de l'équipe ont montré qu'elle peut agir indépendamment de son activité catalytique par interaction protéique. Le répresseur transcriptionnel Tricho-Rhino-Phalangeal Syndrome type 1, TRPS1, a été identifié comme un partenaire potentiel de la cathepsine D. Différentes études indiquent que des cystéines cathepsines peuvent être localisées au noyau et être protéolytiquement actives. Par exemple, la cystéine cathepsine L agit par protéolyse limitée sur le facteur de transcription CDP/Cux et sur l'histone H3 lorsqu'elle est localisée au noyau.Dans cette thèse nous avons étudié le rôle de la cathepsine D nucléaire dans des cellules cancéreuses mammaires. Nos résultats indiquent que la cathepsine D, comme TRPS1, est localisée au noyau et est associée à la chromatine dans les cellules positives aux récepteurs aux œstrogènes. De plus elle interagit de manière directe et endogène avec TRPS1 et participe à la régulation transcriptionnelle de PTHrP (parathyroïd hormone-related protein) un gène cible de TRPS1. Finalement nous avons identifié de nouveaux gènes co-régulés par TRPS1 et la cathepsine D dans le cancer du sein montrant que leur action n'est pas limitée à PTHrP. L'ensemble de ces résultats suggère que la cathepsine D est la première cathepsine identifiée comme un co-facteur transcriptionnel et que son rôle dans le cancer pourrait impliquer, en plus de ses activités extracellulaires, ses activités nucléaires. / Cathepsin D is a lysosomal aspartyl protease which is overexpressed and hyper-secreted by epithelial breast cancer cells. This is a poor prognosis factor in breast cancer. It stimulates cancer cell proliferation and metastasis formation. Team works have shown it can acts in an independent manner of its catalytic activity by protein interactions. The transcriptional repressor trichorhinophalangeal syndrome type 1 protein, TRPS1, has been identified as a new potential partner of Cathepsin D. Several studies indicate that cystein cathepsins can be localized in nucleus and are proteolytically actives. For example, the cystein Cathepsin L acts by limited proteolysis of the CDP/Cux transcription factor and histone H3 when located to the nucleus.During this thesis, we studied the role of nuclear Cathepsin D in breast cancer cells. Our results indicate that Cathepsin D, as TRPS1, is localized in nucleus and is associated with chromatin in estrogen-receptor positive breast cancer cells. Furthermore it interacts in a direct and endogenous manner with TRPS1 and participates to the transcriptional repression of PTHrP, parathyroïd hormone-related protein, a TRPS1 target gene. Finally, we identified new co-regulated genes by TRPS1 and Cathepsin D in breast cancer showing their action is not limited to PTHrP.Together, our results suggest that Cathepsin D is the first cathepsin identified as a transcriptional co-repressor and that its role in cancer may involve, in addition to its extracellular activities, its nuclear activities.

This paper analyzes the utilization of repression and democratic institutions by a non-democratic government striving for political power and private rents. We find that economic development has different impacts on policy choices, depending on whether it appears in the form of rises in income or in education: A higher income level reduces democracy, whereas more education leads to both more democracy and more repression. These theoretical findings are corroborated by panel data regressions.

The CCAAT binding-factor (CBF) is a transcriptional activator conserved in eukaryotes. The CBF in Saccharomyces cerevisiae is a multimeric heteromer termed the Hap2/3/4/5 complex. Hap4, which contains the activation domain of the complex, is also the regulatory subunit and is known to be transcriptionally controlled by carbon sources. However, little is known about Hap4 regulation. In this report, I identify mechanisms by which Hap4 is regulated, including: (1) transcriptional regulation via two short upstream open reading frames (uORFs) in the 5' leader sequence of HAP4 mRNA; (2) proteasome-dependent degradation of Hap4; and (3) identification of two negative regulators of HAP4 expression, CYC8 and SIN4. I also report differential patterns of Hap4 cellular localization which depends on (1) carbon sources, (2) abundance of Hap4 protein, and (3) presence or absence of mitochondrial DNA (mtDNA).