Oncogenic activation of a human cyclin A2 targeted to the endoplasmic reticulum upon hepatitis B virus genome insertion.
Cyclins are major cell cycle regulators which role in malignant transformation remains controversial. In this report we describe a new mechanism of cyclin oncogenic activation. We demonstrate that an altered form of cyclin A2 (S2A) which N-terminal part is replaced by the hepatitis B virus envelope protein transforms normal rat kidney cells and cooperates with ras to transform rat embryo fibroblasts. In contrast, neither the viral moiety, nor a full length or N-terminally deleted cyclin A2 show these oncogenic properties. S2A oncogenicity arises from its binding to cyclin dependent kinases, since mutation in the MRAIL sequence abolishes transformation and correlates with an abnormal cellular localization in the endoplasmic reticulum membrane. Together, these results implicate modification in the cellular distribution of a cell cycle regulator as a mechanism of virally-induced transformation.
Berasain
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C
INSERM U370 and Liver Unit, Necker Institute and Hospital, Paris, France.
Patil
D
D
Perara
E
E
Huang
S M
SM
Mouly
H
H
Bréchot
C
C
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D019925:Cyclin A / Q000096:biosynthesis* / Q000737:chemistry; D056751:Cyclin A2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D017931:DNA Primers; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts; D011905:Genes, ras; D005822:Genetic Vectors; D016679:Genome, Viral; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D014176:Protein Biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D017384:Sequence Deletion; D014158:Transcription, Genetic; D014162:Transfection / Q000379:methods; D014183:Transplantation, Heterologous
C503721:CCNA2 protein, human; C503722:Ccna2 protein, rat; D019925:Cyclin A; D056751:Cyclin A2; D017931:DNA Primers; D011994:Recombinant Proteins; D018844:Cyclin-Dependent Kinases