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THE COUNCIL FOR TOBACCO RESEARCH-U.S.A., INC. MemorandLUn Zb: Dr. H.McAllister and Staff Fran: D.H.Ford Re: Site visit with Dr.Paula EYirietto, State University of New York at Stony Brook, NY, May 20, 1992. Grant No. 3196 entitled "Identification of rel-regulated genes." Goals: The overall goal for Dr. Enrietto is to identify those genes whose expression is regulated by v-rel, and which presumably are important in the oncogencic transformation of the lymphoid cells in youmg birds to a rapidly fatal leukemia. Results: In order to undertake this program, Dr. Enrietto has created a ch~ric gene containing v-rel + the honncne binding danain of the human estrogen receptor. Thus, the activity of the gene becames inducible by estrogen and she will be able to determine which genes are turned on or off by v-rel in the presence of estrogen. The cell type which she will use appears to be a stem cell for the hematopoietic system which will give rise to both lymphoid and erythroid cell types. An additicaZal oell which appears in the culture system resembles a megakaryocyte, but is not yet clearly identified as such. In the presence of estrogen, the v-rel/human estrogen binding dcxna.in catiplex bind to some canponent of the stem cell cytoplasm and to the nucleus; it binds to DNA, regulates gene expression and induces cell transformation. In the absence of estrogen, the canplex only binds to some cytoplasmic oanponent and to some site in the nucleus, but does not bind to DNA or have any effect on gene expression or transformation into one or another of the cell types of the hematopoietic system. Dr. Fhrietto has.just initiated the creation of the cDNA libraries fran the various cell types"whicr,h are induced in the presence of estrogen in the culture.. and hopes to determine which genes are turned off or on by the presence of the hormone, and, as a result•to determine which genes regulate v-rel expression. So far she has determined that the gene regulates.,in the the presence of estrogencode for MHC Class I, _ a genec involved in chrcmatin structure and the gene which codes for a marker protein 14c47/83. The first two genes have already been cloned. Her expreience with this system so far suggests that the effect of v-rel on other genes may be to either suppress or activate their expression, depending on the gene involved. The protein whose synthesis is directed by rel may be one of a family of at least 10, which appear to have different specificties of binding to NF-KB binding sites. While this is clearly a program directed toward the role of rel in regulating genes which may be involved in oncogenesis, it is also a program concerned with how rel-regulated genes are invovled in normal cell transformation fran stem cells to those which are differenii.ated for specific functions, as would occur among cells derived fran a hematopoeitc stem cell. Discussion: Dr. IIhrietto is a young enthusiastic well trained individual who, unlike many of our younger researchers, has been well trained in all the basic fields of inedicine (first 2 years). Thus, while her program may use the tools of molecular biology, she is clearly able to grasp the related significance of structure;-'endocrine effects (perhaps as related to CNS influences on pituitary function and auta--anic influences on t may happen to influence differentiationof stem cells in the bone marrow`3~ile this program was obviously well along when she obtained CTR support, it appears that she has made excellent progress since the initiation of CTR support. DHF