Interplay of heavy metal homeostasis and cell growth-related signaling networks

PROJECT SUMMARY Heavy metals are natural components in the earth but become concentrated and toxic in environment as a result of human-­caused activities. The term heavy metals comprise a number of essential metals (e.g. zinc, copper, iron) and non-­essential metals (e.g. cadmium, mercury, lead) for human, whose excess results in toxicity even under trace amount. Accumulated heavy metals directly bind to and interfere with various cellular components (e.g. proteins, nucleic acids), and lead to severe cellular dysfunction and even death. The most commonly affected organs include liver, kidney, intestine, heart, blood and nervous systems. Children with their developing nervous systems are particularly vulnerable to heavy metal intoxication. Heavy metal homeostasis also plays an essential role in human normal physiology, whose defect results in various human diseases. Therefore, understanding the fine-­tuned cellular response to overdosed heavy metals will lead to the development of effective therapeutic methods against heavy metal-­associated intoxication and diseases. In this application, we propose to elucidate the molecular mechanism involved in heavy metal response by establishing the Hippo pathway as a key player in this process. Over the past decades, the Hippo pathway has been recognized as a crucial signaling pathway that controls tissue/organ size by restricting cell proliferation and stimulating cell apoptosis. Interestingly, our preliminary studies have revealed an unexpected role of the Hippo pathway in heavy metal response by regulating metal-­responsive transcription factor 1 (MTF1). Moreover, we have revealed a novel regulation of the Hippo pathway by heavy meals. Based on these findings, we hypothesize that the Hippo pathway plays a critical role in heavy metal response. In this application, we propose 1) to characterize the Hippo pathway-­mediated heavy metal response in vivo (Aim 1);; 2) to elucidate the regulation of MTF1 by the Hippo pathway (Aim 2);; and 3) to study the regulation of the Hippo pathway by heavy metals (Aim 3).