This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.
The specific aims have been slightly modified from those proposed in the original application. Sphingomyelin synthase (SMS) represents an important class of enzymes responsible for sphingomyelin (SM) biosynthesis. In particular, SMS transfers a phosphorylcholine moiety from phosphatidylcholine (PC) to ceramide to form SM and diacylglycerol (DAG). Therefore SMS not only produces SM, a crucial phospholipid for the integrity of cellular membranes but also regulates in opposing directions the levels of two bioactive lipids with opposing functions such as DAG and ceramide. Ceramide is an established negative regulator of cell proliferation whereas DAG is a well-accepted mitogenic factor.Previous studies conducted by the PI showed that activation of SM synthesis resulted in activation of NF-kB, a pivotal transcription factor, involved in the regulation of important cellular functions, including cell survival and inflammatory responses.Recently, the cloning of candidate SMSs led to the identification of two mammalian genes (SMS1 and SMS2) that, when expressed in yeast cells, encoded for proteins with SMS activity. Our preliminary results confirmed the different localization of the two putative SMSs. They also pointed to a physiologic role for both SMS1 and SMS2 as bona fide SMSs in mammalian cells. Interestingly, we found that knock-down of SMS1 impaired activation of NF-kB. Based on the potential role of SMS1 in promoting NF-kB activation and because NF-kB activation is a key component of the cellular response to cytokine signaling, we hypothesize that SMS1 regulates activation of NF-kB through modulation of the bioactive lipids controlled by its biochemical reaction, and that SMS1, through activation of NF-kB, is a determinant for cytokine signaling. In order to test our hypothesis, we will determine the biochemical function of human SMS1 and SMS2 in mammalian cells and establish the role and function of SMS1 in the regulation of NF-kB.
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