Evolution of the oncogenic potential of v-rel: rel-induced expression of immunoregulatory receptors correlates with tumor development and in vitro transformation.
v-rel is a viral oncogene that evolved from turkey c-rel, an NF-kappa B-related transcription factor. Numerous structural alterations record the evolutionary selection of v-rel and distinguish it from c-rel. To evaluate the biological significance of these alterations, we constructed a set of five c/v-rel hybrids in which three mutation clusters (c-Rel amino acids 1 to 97,222 to 302, and 328 to 598) were differentially distributed. These constructs, in addition to parental v-rel and c-rel and two C-terminal deletion mutants of c-rel, were expressed from a retroviral vector. An analysis of cells infected with each of the nine viruses revealed that mutations in all three domains contributed to the ability of v-rel to induce two endogenous c-rel target genes, major histocompatibility complex (MHC) class I and class II, in the B-cell line DT95 as well as MHC class II in normal splenocytes. The analysis revealed a strong nonlinear correlation between the ability of a Rel protein to induce expression of MHC proteins and its capacity to produce splenic tumors and establish in vitro transformation. This correlation is consistent with the hypothesis that v-rel transforms by constitutively altering expression of genes regulated by c-rel and in this way simulates events associated with immune response-linked proliferation of cells of hematopoietic origin. Further, the 16 carboxy-terminal amino acids of c-Rel were identified as a domain responsible for producing a cytotoxic and/or cytostatic effect in DT95. Because this effect is likely to differentially influence induction of MHC expression and tumorigenesis/transformation, it may represent one factor that contributes to the nonlinearity of their correlation.
Nehyba
J
J
Mary Babb Randolph Cancer Center, West Virginia University, Morgantown 26506-9300.
Hrdlicková
R
R
Humphries
E H
EH
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000473:pathology; D001483:Base Sequence; D005075:Biological Evolution; D002471:Cell Transformation, Neoplastic; D002642:Chick Embryo; D002645:Chickens / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology*; D020572:Oncogene Proteins v-rel; D009857:Oncogenes / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020569:Proto-Oncogene Proteins c-rel; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017986:Reticuloendotheliosis Viruses, Avian / Q000235:genetics; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics*; D013154:Spleen / Q000166:cytology / Q000473:pathology
D006649:Histocompatibility Antigens; D020572:Oncogene Proteins v-rel; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D011993:Recombinant Fusion Proteins; D015682:Retroviridae Proteins, Oncogenic