ENERGY RESTRICTION, CELL SIGNALING AND CANCER PREVENTION

描述：拟议的研究将测试饮食

DESCRIPTION: The proposed studies will test the hypothesis that dietary energy restriction (ER) inhibits skin tumor promotion by elevating glucocorticoid hormone (GCH) which reduces selected epidermal protein kinase C (PKC alpha and zeta) and blocks AP-1 induction. The first specific aim will determine if the adrenal gland is required for ER inhibition of tumor promotion and if administration of GCH to adrenalectomized/ER mice restores the ER inhibition. Skin tumors will be initiated with 7,12-dimethyl benz(a)anthracene (DMBA) and promoted with TPA. Elevation of GCH is hypothesized to mediate the inhibition of skin tumor promotion by causing the reduction in PKC protein levels which inhibits signaling down Raf-1/MAP-Kinase pathways and blocks the ability of TPA to induce c-June protein and AP-1:DNA binding. Specific Aim 2 will test the hypothesis that the blockage of the induction of AP-1:DNA binding is dependent upon ER regulation of constituent proteins of AP-1. The third specific aim will test the hypothesis that ER blocks signaling down the Raf-1/MAP-kinase pathway at the level of Raf-1, a well known substrate for PKC. Gel mobility shift experiments with AP-1 DNA consensus sequences, western blots and immune complex kinase assays will be used for Aims 2 and 3. In the fourth specific aim, the ability of dietary energy restriction to block AP-1 induction and transcriptional regulation of luciferase in TPA and UVB-light treated mice will be investigated using the transgenic AP-1-luciferase mouse model. The dependence of the biochemical events modified in Aims 2-4 on corticosterone will be assessed by parallel studies in sham and adrenalectomized mice.