There is rapidly evolving evidence for beneficial retinoid actions in preventing or treating clinical tumors. This application explores a novel all-trans-retinoic acid (RA)- dependent G1 cell cycle arrest mechanism active in preventing carcinogenic transformation of human bronchial epithelial cells. Preliminary findings indicate that using cultured human bronchial epithelial cells that RA-treatment engages the G1 cell cycle machinery to trigger growth arrest and antagonize carcinogenic transformation. Interest in studying this further is propelled by our unexpected finding that retinoids signal G1 arrest through a pharmacological mechanism: proteolysis of G1 cyclins via ubiquitin-dependent degradation of G1 cyclins. This RA-triggered G1 arrest is hypothesized to permit repair of genomic damage by carcinogens. This proposal explores whether retinoid-dependent degradation of G1 cyclins is a cancer chemoprevention mechanism through these specific aims: (1) To define precisely the retinoid chemoprevention mechanism inducing ubiquitin-dependent proteolysis of G1 cyclins in human bronchial epithelial cells through these questions: (a) Does RA affect stability of wild- type versus ubiquitin-degradation resistant cyclin D1 and E proteins? (b) Does RA affect directly ubiquitination of these G1 cyclins? (c) Does RA signal phosphorylation of these G1 cyclins at sites involved in ubiquitination: and (d) Does RA regulate in these cells ubiquitin-ligase components induced by RA in other cell contexts? (2) To determine whether this ubiquitin-dependent proteolysis of G1 cyclins is required for retinoid suppression of bronchial epithelial cell transformation by: (a) assaying transformation of human bronchial epithelial cells engineered to over-express wild-type and/or degradation resistant G1 cyclins; (b) exploring whether RA or other prevention agents overcome this G1 cyclin-dependent transformation through a ubiquitin- degradation mechanism; and (c) transfecting antisense constructs for these G1 cyclins into human bronchial epithelial cells to establish whether this mimics RA effects. (3) To establish the in vivo relevancy of these findings using bronchial tissues derived during a clinical chemoprevention trial to determine that basal G1 cyclin expression in neoplastic lung tissues is repressed by retinoid treatment. In this proposal, cellular, biochemical, and molecular genetic techniques are used to investigate in unique preclinical experimental models how retinoids act in lung cancer prevention. Successful completion of these aims should lead to an improved understanding of how RA exerts its anti-carcinogenic actions in cancer prevention models. Studies of retinoid signaled cell cycle control mechanisms are relevant to learning how retinoids act in cancer therapy or prevention.
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