Transforming growth factor beta1 receptor II is downregulated by E1A in adenovirus-infected cells.
Transforming growth factor beta1 (TGF-beta1) signaling is compromised in many tumors, thereby allowing the tumor to escape the growth-inhibitory and proapoptotic activities of the cytokine. Human adenoviruses interfere with a number of cellular pathways involved in cell cycle regulation and apoptosis, initially placing the cell in a "tumor-like" state by forcing quiescent cells into the cell cycle and also inhibiting apoptosis. We report that adenovirus-infected cells resemble tumor cells in that TGF-beta1 signaling is inhibited. The levels of TGF-beta1 receptor II (TbetaRII) in adenovirus-infected cells were decreased, and this decrease was mapped, by using virus mutants, to the E1A gene and to amino acids 2 to 36 and the C-terminal binding protein binding site in the E1A protein. The decrease in the TbetaRII protein was accompanied by a decrease in TbetaRII mRNA. The decrease in TbetaRII protein levels in adenovirus-infected cells was greater than the decrease in TbetaRII mRNA, suggesting that downregulation of the TbetaRII protein may occur through more than one mechanism. Surprisingly in this context, the half-lives of the TbetaRII protein in infected and uninfected cells were similar. TGF-beta1 signaling was compromised in cells infected with wild-type adenovirus, as measured with 3TP-lux, a TGF-beta-sensitive reporter plasmid expressing luciferase. Adenovirus mutants deficient in TbetaRII downregulation did not inhibit TGF-beta1 signaling. TGF-beta1 pretreatment reduced the relative abundance of adenovirus structural proteins in infected cells, an effect that was potentiated when cells were infected with mutants incapable of modulating the TGF-beta signaling pathway. These results raise the possibility that inhibition of TGF-beta signaling by E1A is a means by which adenovirus counters the antiviral defenses of the host.
Tarakanova
Vera L
VL
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA. vera@tarakanov.com
Wold
William S M
WS
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000502:physiology*; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II