Silent point mutation in an avian retrovirus RNA processing element promotes c-myb-associated short-latency lymphomas.
The avian leukosis virus DeltaLR-9 causes a high frequency of B-cell lymphomas within weeks after injection into 10-day-old chicken embryos. These lymphomas result from proviral integrations into the oncogene c-myb. In contrast, LR-9, which lacks the 42-nucleotide gag gene deletion of DeltaLR-9, does not cause a high frequency of c-myb-associated short-latency lymphomas. Although viral replication rates and spliced env mRNA levels were found to be similar for both viruses, DeltaLR-9 exhibited an increase in readthrough transcription compared to LR-9. The DeltaLR-9 deletion is located in the region of the gag gene corresponding to the matrix (MA) protein as well as in the negative regulator of splicing (NRS) element. To test whether disruption of the NRS or of the MA protein was responsible for inducing short-latency lymphomas, we generated viruses with NRS point mutations that maintained the wild-type Gag amino acid sequence. One of the mutant viruses induced an even higher incidence than DeltaLR-9 of short-latency lymphomas with viral integrations into c-myb. Thus, we propose that disruption of the NRS sequence promotes readthrough transcription and splicing to the downstream myb gene, causing overexpression of a slightly truncated Myb protein, which induces short-latency tumors.
Polony
Tatjana S
TS
Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Bowers
Sandra J
SJ
Neiman
Paul E
PE
Beemon
Karen L
KL
D000818:Animals; D001353:Avian Leukosis / Q000209:etiology* / Q000235:genetics / Q000821:virology; D001354:Avian Leukosis Virus / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D001483:Base Sequence; D002642:Chick Embryo; D004279:DNA, Viral / Q000235:genetics; D015752:Genes, env; D020570:Genes, myb; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000235:genetics / Q000821:virology; D020626:Oncogene Proteins v-myb / Q000235:genetics / Q000502:physiology; D017354:Point Mutation; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology; D016662:Virus Integration / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
D004279:DNA, Viral; D020626:Oncogene Proteins v-myb; D012333:RNA, Messenger; D012367:RNA, Viral; D014763:Viral Matrix Proteins