repression of androgen receptor transcription through the e2f1dnmt1 axis通过e2f1dnmt1轴压制雄激素受体的转录.pdfVIP

Repression of Androgen Receptor Transcription through the E2F1/DNMT1 Axis 1 1 1 1 1 Conrad David Valdez , Joanne N. Davis , Hana M. Odeh , Tristan L. Layfield , Craig S. Cousineau , 2 2 1 1 Thomas R. Berton , David G. Johnson , Kirk J. Wojno , Mark L. Day * 1 Department of Urology, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Science Park- Research Division, Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas, United States of America Abstract Although androgen receptor (AR) function has been extensively studied, regulation of the AR gene itself has been much less characterized. In this study, we observed a dramatic reduction in the expression of androgen receptor mRNA and protein in hyperproliferative prostate epithelium of keratin 5 promoter driven E2F1 transgenic mice. To confirm an inhibitory function for E2F1 on AR transcription, we showed that E2F1 inhibited the transcription of endogenous AR mRNA, subsequent AR protein, and AR promoter activity in both human and mouse epithelial cells. E2F1 also inhibited androgen-stimulated activation of two AR target gene promoters. To elucidate the molecular mechanism of E2F-mediated inhibition of AR, we evaluated the effects of two functional E2F1 mutants on AR promoter activity and found that the transactivation domain appears to mediate E2F1 repression of the AR promoter. Because DNMT1 is a functional intermediate of E2F1 we examined DNMT1 function in AR repression. Repression of endogenous AR in normal human prostate epithelial cells was relieved by DNMT1 shRNA kno