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Transforming growth factor beta1 receptor II is downregulated by E1A in adenovirus-infected cells. J Virol 2003 Sep;77(17):9324-36

Date

08/14/2003

Pubmed ID

12915548

Pubmed Central ID

PMC187388

DOI

10.1128/jvi.77.17.9324-9336.2003

Scopus ID

2-s2.0-0042389592   9 Citations

Abstract

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.

Author List

Tarakanova VL, Wold WS

Author

Vera Tarakanova PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenovirus E1A Proteins
Adenoviruses, Human
Cell Line
Down-Regulation
Humans
Mutation
Protein-Serine-Threonine Kinases
RNA, Messenger
Receptors, Transforming Growth Factor beta
Signal Transduction
Transforming Growth Factor beta
Transforming Growth Factor beta1
Virus Replication
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a