The latent membrane protein 1 oncogene modifies B-cell physiology by regulating autophagy.
Epstein-Barr virus (EBV) is a herpes virus that is associated with several human cancers. Infection of B cells by EBV leads to their induction and maintenance of proliferation and requires the oncogene, latent membrane protein 1 (LMP1). LMP1 signals in a ligand-independent manner and is expressed at widely different levels in cells of a single clone. It is this unusual distribution that allows LMP1 to stimulate multiple, distinct pathways. Average levels of LMP1 induce proliferation while high levels induce cytostasis and inhibition of protein synthesis. These inhibitory pathways are induced by the six transmembrane domains of LMP1. We uncovered a novel function encoded by transmembrane domains 3-6 of LMP1; they induce autophagy in a dose-dependent manner and thus, modify the physiology of their host. Cells that express low levels of LMP1 display early stages of autophagy, autophagosomes; those that express high levels of this oncogene display late stages of autophagy, autolysosomes. Inhibition of autophagy in EBV-positive cells leads to an accumulation of LMP1 and a decreased ability to form colonies. These results indicate that LMP1's induction of autophagy contributes to its own regulation and that of its host cell.
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.
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Sugden
D001343:Autophagy / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology* / Q000821:virology; D045744:Cell Line, Tumor; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D009857:Oncogenes / Q000502:physiology*; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000378:metabolism
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins