IN vivo evolution of c-rel oncogenic potential

• Published in: Journal of Virology Vol. 68; no. 4; pp. 2371 - 2382
• Main Authors: Hrdlickova, R, Nehyba, J, Humphries, E.H
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.04.1994
• Subjects: ADN; Alpharetrovirus - genetics; Animals; BAZO; Biological and medical sciences; Biological Evolution; Carcinogenesis, carcinogens and anticarcinogens; CARCINOGENOS; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Chickens; Fundamental and applied biological sciences. Psychology; GENE; GENES; Histocompatibility Antigens - biosynthesis; Interleukin-2 - biosynthesis; Lymphoid Tissue - cytology; Medical sciences; Molecular and cellular biology; MUTACION INDUCIDA; MUTANT; MUTANTES; Mutation; MUTATION PROVOQUEE; NEOPLASMAS; NEOPLASME; Neoplasms, Experimental - genetics; Oncogene Proteins v-rel; ONCOGENICIDAD; ONCOGENICITE; ONCOVIRUS AVIAIRE; ONCOVIRUS AVIAR; Plasmids - genetics; POLLO; POULET; PROTEINAS; PROTEINE; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-rel; Proto-Oncogenes - genetics; RATE; Retroviridae Proteins, Oncogenic - genetics; Sequence Deletion; SUBSTANCE CANCERIGENE; Transformation, Genetic; Tumors; Viruses; Oncovirinae; Gene product; Cell nucleus; Retroviridae; Tumorigenicity; Structure function relationship; Virus; C terminal-Sequence; In vivo; Vertebrata; Cell line; Type C oncovirus; Avian reticuloendotheliosis virus; Chicken; Aves; Onc gene; Localization; Molecular domain; Protooncogene
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/jvi.68.4.2371-2382.1994

The c-rel proto-oncogene belongs to the NF-kappa B/rel and I kappa B gene families, which regulate several inducible processes, including self-defense/repair and embryogenesis. Transduction of the c-rel transcription factor by the avian retrovirus resulted in the formation of a highly oncogenic virus, reticuloendotheliosis virus strain T (REV-T), that encodes the oncogene v-rel. To examine the oncogenic potential of c-rel, we inserted it into a REV-T-based retroviral vector, rescued virus [REV-C(CSV)], and infected 1-day-old chicks. All birds developed tumors, and all cell lines established from REV-C-induced tumors expressed c-rel proteins that lacked C-terminal sequences. These proteins, responsible for both in vivo and in vitro cell proliferation, were apparently selected for their oncogenic potential. In order to examine the cooperation of C-terminal deletions with other oncogenic alterations in vivo, point mutations present in the N-terminal and middle regions of v-rel were analyzed by a similar protocol. The data obtained support four conclusions. (i) c-rel proteins bearing any of three single-amino-acid mutations present in the N-terminal portion of v-rel were sufficiently oncogenic to induce tumor development in the absence of additional mutations. (ii) Combining a mutation from the N-terminal region of v-rel with a deletion of the C-terminal sequences of c-rel increases the oncogenicity of the protein in an additive manner. (iii) Mutations present in the middle of v-rel cooperated synergistically with C-terminal deletions to produce highly transforming viruses. (iv) Deletion of c-rel produced a variety of transforming rel proteins with sizes that extended from 42 to 65 kDa. The most frequently isolated rel deletion was 62 kDa in size. To examine the basis for the selection of different rel mutants, their ability to induce immunoregulatory surface receptors was analyzed