An auto-regulatory loop for EBV LMP2A involves activation of Notch.
LMP2A is consistently detected in Hodgkin's lymphoma, nasopharyngeal carcinoma and has also been detected in Burkitt's lymphoma. Interestingly, LMP2A is detected in the absence of the transcriptional activator EBNA2, suggesting that an alternative mechanism is responsible for LMP2A expression. The intracellular domain of Notch (Notch-IC) and EBNA2 are functional homologs and recent microarray analysis indicates that LMP2A may constitutively activate the Notch pathway in vivo. Coupled with evidence that Notch-IC can bind to and activate the LMP2A promoter, we hypothesized that expression of LMP2A results in the constitutive activation of the Notch pathway to auto-regulate its promoter. Our data indicate that LMP2A constitutively activates the Notch pathway in B cells and epithelial cells. Expression of LMP2A alone is sufficient to activate its own expression and the amino-terminal signaling domain is required as LMP2B is unable to activate the LMP2A promoter. In addition, point mutations in tyrosines 31, 101 and 112 each results in a significant decrease in LMP2A promoter activation. Deletion of the RBP-Jkappa consensus sequences results in a significant decrease in promoter activity. The observation that LMP2A activates its own promoter suggests that LMP2A exploits the Notch pathway in order to control its own expression and may explain EBNA2-independent expression of LMP2A in EBV-associated malignancies.
Anderson
Leah J
LJ
Department of Microbiology and Immunology, Northwestern University, Chicago, Illinois 60611, USA.
Longnecker
Richard
R
D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D014763:Viral Matrix Proteins