Kinetic Analysis of Myc-induced carcinogenesis in vivo

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DESCRIPTION (provided by applicant): Expression of the c-Myc oncoprotein is deregulated or elevated in many human cancers. The surprising discovery that Myc can induce apoptosis, particularly in cells subjected to survival factors, death receptor signals or genotoxic or other stress, raised the possibility that apoptosis might serve as an inbuilt tumor suppressive function that must be overridden before any tumors can emerge. The proclivity of Myc to promote apoptosis in any instance in vivo is critically determined by subtle and lineage-specific interactions between the cell and its local somatic environment that cannot be adequately reproduced in vitro. Unfortunately, Myc-induced apoptosis is so ephemeral that it has not proved possible to observe it directly in transgenic Myc models in which tissue-specific Myc expression has been present throughout ontogeny. Consequently, we can only infer a role for Myc-induced apoptosis in tumor suppression from the observed oncogenic cooperation between Myc and anti-apoptotic lesions. To evaluate directly the influence of Myc-induced apoptosis in Myc-induced tumorigenesis we have built a unique transgenic Myc model in which a reversibly switchable form of the c-Myc protein has been targeted to the beta cells of the pancreas. Acute activation of Myc in adult beta cells triggers a rapid, synchronous and wholesale involution of the beta cell population leading to the acute onset of diabetes. In contrast, suppression of beta cell apoptosis by expression of the apoptosis suppressor Bcl-xL transforms the effect of Myc into a potent and pleiotropic tumor inducer. In this proposal we will validate our switchable beta cell Myc-ER(TM) model and define the role of Myc-induced apoptosis in limiting beta cell tumorigenesis (Aim1). Several discrete effectors are implicated in Myc-induced apoptosis, including the ARF/p53 tumor suppressor pathway, signaling through the Fas/Trail/TNFR death receptors and regulation of mitochondrial status by survival factors and members of the Bcl-2/Bax family. In Aim 2 we will define the contribution of each of these effector systems towards Myc-induced apoptosis and determine the consequences of their ablation for Myc-induced tumorigenesis. Myc-induced beta cell tumors rapidly and completely regress following Myc de-activation. We will use this phenomenon to define the mechanistic requirement for Myc in the maintenance of beta cell tumors and the mechanism by which Myc deactivation triggers tumor regression.