Insulin and TOR pathways regulate cellular and organismal growth through the myc oncogene in Drosophila

A large body of literature documents in both mice and Drosophila the involvement of Insulin pathway in growth regulation, probably due to its role in glucose and lipid import, nutrient storage, and translation of RNAs implicated in ribosome biogenesis (Vanhaesebroeck et al. 2001). Moreover several lines of evidence implicate this pathway as a causal factor in cancer (Sale, 2008; Zeng and Yee 2007; Hursting et al., 2007; Chan et al., 2008). With regards to Myc, studies in cell culture have implied this family of transcription factors as regulators of the cell cycle that are rapidly induced in response to growth factors. Myc is a potent oncogene, rearranged and overexpressed in a wide range of human tumors and necessary during development. Its conditional knock-out in mice results in reduction of body weight due to defect in cell proliferation (Trumpp et al. 2001). Evidence from in vivo studies in Drosophila and mammals suggests a critical function for myc in cell growth regulation (Iritani and Eisenman 1999; Johnston et al. 1999; Kim et al. 2000; de Alboran et al. 2001; Douglas et al. 2001). This role is supported by our analysis of Myc target genes in Drosophila, which include genes involved in RNA binding, processing, ribosome biogenesis and nucleolar function (Orain et al 2003, Bellosta et al., 2005, Hulf et al, 2005). The fact that Insulin signaling and Myc have both been associated with growth control suggests that they may interact with each other. However, genetic evidence suggesting that Insulin signaling regulates Myc in vivo is lacking. In this work we were able to show, for the first time, a direct modulation of dMyc in response to Insulin stimulation/silencing both in vitro and in vivo. Our results suggest that dMyc up-regulation in response to DILPs signaling occurs both at the mRNA and potein level. We believe dMyc protein accumulation after Insulin signaling activation is conditioned to AKT-dependent GSK3β/sgg inactivation. In fact, we were able to demonstate that dMyc protein stabilization through phosphorylation is a conserved feature between Drosophila and vertebrates and requires multiple events. The final phosphorylation step, that results in a non-stable form of dMyc protein, ready to be degraded by the proteasome, is performed by GSK3β/sgg kinase (Sears, 2004). At the same time we demonstrated that CKI family of protein kinase are required to prime dMyc phosphorylation. DILPs and TOR/Nutrient signalings are known to communicate at several levels (Neufeld, 2003). For this reason we further investigated TOR contribution to dMyc-dependent growth regulation. dMyc protein accumulates in S2 cells after aminoacid stimulation, while its mRNA does not seem to be affected upon TORC1 inhibition, suggesting that the Nutrient pathway regulates dMyc mostly post-transcriptionally. In support to this hypothesis, we observed a TORC1-dependent GSK3β/sgg inactivation, further confirming a synergic effect of DILPs and Nutrients on dMyc protein stability. On the other hand, our data show that Rheb but not S6K, both downstream of the TOR kinase, contributes to the dMyc-induced growth of the eye tissue, suggesting that Rheb controls growth independently of S6K.. Moreover, Rheb seems to be able to regulate organ size during development inducing cell death, a mechanism no longer occurring in absence of dmyc. These observations suggest that Rheb might control growth through a new pathway independent of TOR/S6K but still dependent on dMyc. In order to dissect the mechanism of dMyc regulation in response to these events, we analyzed the relative contribution of Rheb, TOR and S6K to dMyc expression, biochemically in S2 cells and in vivo in morphogenetic clones and we further confirmed an interplay between Rheb and Myc that seems to be indipendent from TOR. In this work we clarified the mechanisms that stabilize dMyc protein in vitro and in vivo and we observed for the first time dMyc responsiveness to DILPs and TOR. At the same time, we discovered a new branch of the Nutrient pathway that appears to drive growth through dMyc but indipendently from TOR. We believe our work shed light on the mechanisms cells use to grow or restrain growth in presence/absence of growth promoting cues and for this reason it contributes to understand the physiology of growth control.

Financial Development and Economic Growth: Time Series Evidence from Albania

The main objective of this thesis is to explore the short and long run causality patterns in the finance – growth nexus and finance-growth-trade nexus before and after the global financial crisis, in the case of Albania. To this end we use quarterly data on real GDP, 13 proxy measures for financial development and the trade openness indicator for the period 1998Q1 – 2013Q2 and 1998Q1-2008Q3. Causality patterns will be explored in a VAR-VECM framework. For this purpose we will proceed as follows: (i) testing for the integration order of the variables; (ii) cointegration analysis and (iii) performing Granger causality tests in a VAR-VECM framework. In the finance-growth nexus, empirical evidence suggests for a positive long run relationship between finance and economic growth, with causality running from financial development to economic growth. The global financial crisis seems to have not affected the causality direction in the finance and growth nexus, thus supporting the finance led growth hypothesis in the long run in the case of Albania. In the finance-growth-trade openness nexus, we found evidence for a positive long run relationship the variables, with causality direction depending on the proxy used for financial development. When the pre-crisis sample is considered, we find evidence for causality running from financial development and trade openness to economic growth. The global financial crisis seems to have affected somewhat the causality direction in the finance-growth-trade nexus, which has become sensible to the proxy used for financial development. On the short run, empirical evidence suggests for a clear unidirectional relationship between finance and growth, with causality mostly running from economic growth to financial development. When we consider the per-crisis sub sample results are mixed, depending on the proxy used for financial development. The same results are confirmed when trade openness is taken into account.

Black Hole and Galaxy Growth over Cosmic Time: the Chandra COSMOS Legacy Survey

The study of supermassive black hole (SMBH) accretion during their phase of activity (hence becoming active galactic nuclei, AGN), and its relation to the host-galaxy growth, requires large datasets of AGN, including a significant fraction of obscured sources. X-ray data are strategic in AGN selection, because at X-ray energies the contamination from non-active galaxies is far less significant than in optical/infrared surveys, and the selection of obscured AGN, including also a fraction of heavily obscured AGN, is much more effective. In this thesis, I present the results of the Chandra COSMOS Legacy survey, a 4.6 Ms X-ray survey covering the equatorial COSMOS area. The COSMOS Legacy depth (flux limit f=2x10^(-16) erg/s/cm^(-2) in the 0.5-2 keV band) is significantly better than that of other X-ray surveys on similar area, and represents the path for surveys with future facilities, like Athena and X-ray Surveyor. The final Chandra COSMOS Legacy catalog contains 4016 point-like sources, 97% of which with redshift. 65% of the sources are optically obscured and potentially caught in the phase of main BH growth. We used the sample of 174 Chandra COSMOS Legacy at z>3 to place constraints on the BH formation scenario. We found a significant disagreement between our space density and the predictions of a physical model of AGN activation through major-merger. This suggests that in our luminosity range the BH triggering through secular accretion is likely preferred to a major-merger triggering scenario. Thanks to its large statistics, the Chandra COSMOS Legacy dataset, combined with the other multiwavelength COSMOS catalogs, will be used to answer questions related to a large number of astrophysical topics, with particular focus on the SMBH accretion in different luminosity and redshift regimes.