An association between viral genes and human oncogenic alterations: the adenovirus E1A induces the Ewing tumor fusion transcript EWS-FLI1.
Malignant transformation of human cells requires the accumulation of multiple genetic alterations, such as the activation of oncogenes and loss of function of tumor suppressor genes or those related to genomic instability. Among the genetic alterations most frequently found in human tumors are chromosomal translocations that may result in the expression of chimeric products with transforming capability or are able to change the expression of oncogenes. We show here that the adenovirus early region 1A (E1A) gene can induce a specific human fusion transcript (EWS-FLI1) that is characteristic of Ewing tumors. This fusion transcript was detected by RT-PCR in normal human fibroblasts and keratinocytes after expression of the adenovirus E1A gene, as well as in human cell lines immortalized by adenoviruses. Cloning and sequencing of the RT-PCR product showed fusion points between EWS and FLI1 cDNA identical to those detected in Ewing tumors. In addition, we detected a chimeric protein by western blot analysis and immunoprecipitation and a t(11,22) by fluorescent in situ hybridization. This association between a single viral gene and a specific human fusion transcript indicates a direct link between viral genes and chromosome translocations, one of the hallmarks of many human tumors.
Sanchez-Prieto
R
R
Department of Pathology, Clinica Puerta de Hierro, San Martin de Porres 4, 28035 Madrid, Spain.
de Alava
E
E
Palomino
T
T
Guinea
J
J
Fernandez
V
V
Cebrian
S
S
LLeonart
M
M
Cabello
P
P
Martin
P
P
San Roman
C
C
Bornstein
R
R
Pardo
J
J
Martinez
A
A
Diaz-Espada
F
F
Barrios
Y
Y
Ramon y Cajal
S
S
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D000260:Adenoviruses, Human / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D005814:Genes, Viral / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015603:Keratinocytes; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics* / Q000502:physiology; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics
D017500:Adenovirus E1A Proteins; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors