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Age-associated dysfunction of retinal pigment epithelial cells (RPEs) is considered to be the initial trigger of retinal diseases such as age-related macular degeneration. Although autophagy is upregulated in RPEs during the course of aging, little is known about how autophagy is regulated and its functional role in RPEs. In this study, we found that expression of Sirtuin 6 (SIRT6) and autophagic markers are upregulated in RPEs of aged mice where subretinal deposition of amyloid-β is accumulated and in amyloid-β stimulated RPEs. In addition, gain and loss-of-function studies confirmed the positive role of SIRT6 in regulating autophagy. Interesting, inhibition of autophagy attenuates amyloid-β stimulated inflammatory response in RPEs. Collectively, our findings uncover the autophagy modulated by SIRT6 may be a proinflammatory mechanism for amyloid-β induced RPE dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: Progesterone (Pg) is an essential steroid hormone during mammary gland development and tumorigenesis, including the maintenance of epithelial stem/progenitor cells. Pg functions through interaction with the progesterone receptors (PR) and Pg-PR signaling is thought to be mediated by key transcription factors, which are largely unidentified. In this study, we have identified the ATBF1 transcription factor as a transcriptional target of Pg-PR signaling in mammary epithelial cells. Pg treatment dramatically increased ATBF1 expression at both mRNA and protein levels in cultured cells and mammary tissues. As expected, the induction of ATBF1 was PR-dependent, as it only occurred in PR-positive but not in PR-negative cells, and pretreatment with the Pg antagonist RU-486 or RNAi-mediated knockdown of PR abolished the upregulation of ATBF1 by Pg. Promoter-reporter and ChIP assays further showed that Pg-activated PR directly binds to the ATBF1 promoter to induce its transcription. Prevention of ATBF1 induction inhibited the function of Pg in promoting progenitor cell transition, as indicated by colony formation in a Matrigel culture assay and expression of stem cell markers CD49f and CD44. These findings suggest that ATBF1 plays a crucial role in the Pg-PR signaling pathway in mammary epithelial cells. [Copyright &y& Elsevier]