Role of a novel MYC/BCL2 pathway in apoptosis and transformation

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DESCRIPTION (provided by applicant): Aberrant expression of the MYC oncoprotein is among the most common causative events in human cancer. Paradoxically, the ability of MYC to drive cell cycle progression is matched by an equally potent capacity for inducing apoptosis. The biochemical signals that dictate whether MYC drives proliferation or apoptosis remain poorly understood. However, the ability to specifically activate MYC's latent apoptotic potential, (also referred to as "intrinsic tumor suppression activity"), is widely regarded as an attractive therapeutic goal. It is clear from a variety of human and mouse genetic studies that the pro- survival BCL2 protein plays a critical role in blocking MYC's intrinsic tumor suppression activity. We have identified biochemical events in the BCL2 pathway that are controlled by MYC, and which are critical for making the decision between tumor cell survival and apoptosis. This advance is based on our identification of the link between MYC, the MIZ1 transcription factor and the transcription of the BCL2 locus. MIZ1 normally activates BCL2 transcription and MYC blocks this activation when inducing apoptosis. It is clear that this pathway must be compromised in tumor cells since they do not exhibit spontaneous apoptosis in response to MYC overexpression. Notably, we have shown that mimicking the reactivation of this pathway by using small molecules to inhibit BCL2 or by shRNA-mediated depletion, completely restores apoptotic function. A deeper understanding of the biochemical events that comprise this pathway may thus help identify points at which therapeutic strategies might be aimed (Aim 1). If human tumors overexpressing MYC are to be selectively triggered to undergo apoptosis via functional inactivation of this single, previously unrecognized node in the MYC, we must test whether this new pathway plays a role in modulating MYC activity in tumors in vivo using animal models (Aim 2). PUBLIC HEALTH RELEVANCE: Normal human cells contain a pathway that causes them to commit suicide (or apoptosis) when they inappropriately express an oncogene. We have identified how this pathway functions in response to the most common human oncogene, MYC and current efforts are aimed at understanding whether cancer cells can be specifically targeted to activate the cell death pathway.