Targeting ATF5 for intervention in brain cancer

University Of California At Davis, Davis CA

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Abstract

Aggressive and unfortunately numerous in the clinic, glioblastoma multiforme is a common form of primary brain tumor, necessitating the development of novel therapies to combat its relentless disease process. Preliminary results from our lab show that downregulation of Activating Transcription Factor 5 (ATF5), a cAMP response element binding protein, suppresses proliferation in cell culture. We will determine whether or not loss of function of ATF5 will reduce their proliferation and trigger apoptosis in tumors of transgenic mice that overexpress dominant negative (d/n) ATF5 transgene through an inducible TetO promoter. We hypothesize that loss of endogenous ATF5 activity in the context of cancer will demonstrate its potential as a novel prospective therapeutic target for anti-neoplastic agents, since ATF5 is found in most cancers including glioblastoma. Artificial induction of tumors through two routes of tumorigenesis will be created by retroviral injection of PDGF to demonstrate an amplified growth factor pathway, and by ethylnitrosourea (END) to simulate environmental exposure to a carcinogen. Our expectation is that its expression will result in destruction of tumor cells in both populations.